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Radiometals in Imaging and Therapy: Highlighting Two Decades of Research

Division of Nuclear Medicine, Department of Radiology, Mayo Clinic, Rochester, MN 55905, USA
Author to whom correspondence should be addressed.
Pharmaceuticals 2023, 16(10), 1460;
Submission received: 17 August 2023 / Revised: 3 October 2023 / Accepted: 5 October 2023 / Published: 13 October 2023


The present article highlights the important progress made in the last two decades in the fields of molecular imaging and radionuclide therapy. Advancements in radiometal-based positron emission tomography, single photon emission computerized tomography, and radionuclide therapy are illustrated in terms of their production routes and ease of radiolabeling. Applications in clinical diagnostic and radionuclide therapy are considered, including human studies under clinical trials; their current stages of clinical translations and findings are summarized. Because the metalloid astatine is used for imaging and radionuclide therapy, it is included in this review. In regard to radionuclide therapy, both beta-minus (β) and alpha (α)-emitting radionuclides are discussed by highlighting their production routes, targeted radiopharmaceuticals, and current clinical translation stage.

1. Introduction

External radiation therapy is a common and effective treatment for various cancers. Radiation therapy was first applied over 100 years ago, immediately after the discovery of the X-ray [1]. Clinicians used it for the treatment of skin diseases, lupus, and other lesions [2,3,4,5]. However, due to the collateral damage and resulting side effects, including hair loss, blurry vision, and dry and itchy skin, its application stalled and triggered the need for an alternative treatment option [6].
In the last two decades, nuclear medicine, including radionuclide therapy, has observed significant growth and development: newer radiopharmaceuticals have been introduced, and their applications in imaging and targeted radionuclide therapy have been diverse [7]. Targeted radionuclide therapy (TRT) has great potential to destroy even the smallest clusters of metastatic cancer cells present anywhere in the body, which is hard to achieve with either external beam radiation therapy or surgery. Therefore, TRT has been clinically used to treat numerous malignancies, such as neuroblastoma, along with breast, thyroid, and prostate cancer [7,8,9]. Treatments using TRT have been explored with and without additional treatment options, such as surgery and chemotherapy.
Typically, therapeutic radiopharmaceuticals consist of four components: (i) a therapeutic radioactive isotope (e.g., 177Lu, 67Cu, 90Y, 212Pb, 212Bi, 225Ac, 223Ra, etc.), (ii) a chelator, (iii) a linker, and (iv) a targeting vector, which delivers the isotope to the affected organs/tissues for treatment. The targeting vector could be a monoclonal antibody (mAb), antibody (Ab) fragment (diabody, nanobody, or single chain variable fragment), protein, aptamer, peptide, extracellular vesicle, virus, or simply a small molecule, such as an inhibitor [7]. Radiometal-based imaging and diagnostic radiopharmaceuticals can be categorized as (i) positron emission tomography (PET) radiopharmaceuticals (bioactive molecules labeled with positron-emitting [β+] isotopes) or (ii) single photon emission computed tomography (SPECT) radiopharmaceuticals (bioactive molecules labeled with gamma-emitting [γ] isotopes). Depending on the type of radiation-emitting isotopes, the therapeutic radiopharmaceuticals can be subdivided into (i) alpha (α) particle-emitting targeted radiopharmaceuticals, (ii) beta minus (β) particle-emitting targeted radiopharmaceuticals, and (iii) Meitner−Auger electron (MAE)-emitting radiopharmaceuticals [10]. Additionally, when radiopharmaceuticals are radiolabeled with both the diagnostic (imaging) and therapeutic isotopes, which could use the same element (64Cu/67Cu, 86Y/90Y, 44/43Sc/47Sc) or different elements (64Cu/212Pb, 68Ga/177Lu, 68Ga/223Ra), they are called “theranostic radiopharmaceuticals.” Depending on the plasma half-life of the targeting vector and the application (imaging/therapy), an appropriate radionuclide should be selected for radiolabeling. This article covers advancements made in radiometal-based diagnostic and therapeutic radiopharmaceuticals in the last two decades.

2. Diagnostic Radionuclides

PET and SPECT are radionuclide-based imaging modalities used routinely in nuclear medicine practice that fall under the category of “molecular imaging” because their radiotracers provide information about particular biological processes at the cellular and molecular levels.
PET measures the energy produced by the two gamma photons (511 keV) that result from annihilation of the positron emitted from the PET radionuclide with atomic electron [11]. The emitted gamma photons are detected with γ-cameras, also called scintillation detectors, which produce reconstructed three-dimensional images depicting the spatial distribution of radiotracers [11]. The common examples of PET probes includes [18F]FDG, [13N]NH3, [68Ga]Ga-PSMA, and [18F]NaF. Preclinical animal PET and clinical PET scanners offer spatial resolution of 1–2 mm and 6–10 mm, respectively, with high sensitivity of 10−11–10−12 mol/L. This level of sensitivity is sufficient to detect biological changes in an organ or tissue to identify the onset of a disease before anatomical changes occur [12].
SPECT measures the single gamma photons emitted directly from γ-emitting radionuclides called SPECT radiopharmaceuticals. The conventional clinical SPECT scanners have lower sensitivity (10−10–10−11 mol/L) and lower spatial resolution (7–15 mm) compared to PET scanners due to the limited performance of collimators [12,13,14]. Despite this, SPECT is the most routinely used nuclear imaging procedure in the clinic and is less expensive compared to PET. The most common SPECT isotopes are 111In, 99mTc, 123/131/125I, and 67Ga.
Recent advances in SPECT γ-cameras, collimators, and reconstruction algorithms have enhanced the spatial resolution and sensitivity of SPECT scanners, allowing for the imaging of a wide range of isotope energy (20–300 keV) [15,16]. Nevertheless, both PET and SPECT need either computed tomography (CT) or magnetic resonance imaging (MRI) for accurate anatomical information. Interestingly, PET cannot distinguish between two different PET probes when injected simultaneously because it measures two γ-rays with the same energy (511 keV); meanwhile, SPECT does have multiplexing capabilities because each radionuclide produces different γ-rays, enabling it to image different targets simultaneously [17].

3. Therapeutic Radionuclides

As stated previously, therapeutic radionuclides emit α particles, β particles, and/or low-energy MAEs (non-energetic particles).
Beta minus emitters can be either of a high energy (90Y, Eβmax = 2.28 MeV,) or a low energy (177Lu, Eβmax = 496 keV), with tissue penetration ranges between 12 mm and 1.5 mm, respectively [18]. Given the long penetration depth of 0.2–12 mm and the moderate linear energy transfer (LET) radiation of ~0.2 keV/µm, β emitters are more suited to treating large-sized tumors (>0.5 cm), and they are considered the current gold standard in targeted radionuclide therapy [19,20].
Alpha emitters emit α particles with high LET energies of 50–230 keV/µm and shorter penetration depths of 50–100 µm (i.e., 5–10 cell diameters) [21]. Alpha radionuclide-based targeted therapy is called targeted alpha therapy (TAT), and it is well suited for the treatment of hematological disease, small tumors, metastasis, and isolated cancer cells. Alpha emitters are perceived as a better therapeutic alternative to beta emitters due to their high LET and short tissue penetration range.
Meitner−Auger electrons are low-energy electrons that can penetrate up to the subcellular nanometer range (<0.5 µm), resulting in a high LET of 4–26 keV/µm [22]. Given the low tissue penetration range and high LET in an extremely small area, MAE emitters could be highly valuable for treating metastatic cancers if delivered selectively within the nucleus of the cancer cells [22]. Figure 1 explains the difference between LET, pathlength (penetration range), and the usefulness of α and β radionuclide therapies.

4. Positron Emitters

4.1. Radioisotopes of Copper

4.1.1. General Information

Among the long list of radioisotopes of copper (Cu), 60Cu, 61Cu, 62Cu, and 64Cu are used for diagnostic imaging, while 64Cu and 67Cu are applied in radionuclide therapy [23]. 64Cu decays by both β+ (~17%) and β (~38%), making it applicable for PET imaging and targeted radionuclide therapy; therefore, it is considered a theranostic radionuclide [24]. In addition, 64Cu also decays by electron capture (EC), which results in a cascade of Auger electrons [22,24]. The decay characteristics of Cu radioisotopes are mentioned in Table 1.

4.1.2. Growth and Advancement of Radiopharmaceuticals Labeled with Copper-Radioisotopes in Clinical Practice

In 1997, [62Cu]Cu-diacetylbis(4-methylthiosemicarbazone), also known as [62Cu]Cu-ATSM, was first discovered as a hypoxia imaging agent in a rat model of cardiac ischemia [26]. Later, other Cu isotopes, including 60/61/64Cu, were used to radiolabel ATSM and employed for imaging of hypoxic solid tumors, with a similar uptake and clearance profile in patients [27,28,29,30,31].
Considering the longer half-life of 64Cu, [64Cu]Cu-ATSM was applied as a hypoxia imaging radiotracer in rectal cancer (National Clinical Trial (NCT) 03951337) [32]. However, several debatable preclinical studies highlighted its lower uptake in hypoxic tumors [28]. The therapeutic potential of [64Cu]Cu-ATSM was first studied in 2001, where it resulted in a six-fold increase in the survival of 50% of hamsters bearing human GW39 colon cancer [33]. Later, several additional preclinical studies supported the theranostic potential of [64Cu]Cu-ATSM to treat various colon carcinoma xenografts (Colon-26, HT-29). In addition to preclinical studies, clinical studies are needed to prove its true theranostic value [34,35,36].
During the last two decades, various 64Cu-labeled Abs have been developed for immuno-PET imaging [37,38,39]. Among them, [64Cu]Cu-DOTA-trastuzumab showed promising clinical utility in identifying HER2+ tumors with high sensitivity (~89%) in breast cancer patients [40,41].
Currently, commonly used somatostatin radiotracers for neuroendocrine tumor (NET) diagnosis are [111In]In-DTPA-octreotide [42], [99mTc]Tc-EDDA/HYNIC-TOC [43], and [68Ga]Ga-DOTATOC [44], with first-in-human studies reported in the years 1993, 2005, and 2001, respectively. During 2012–2017, Pfeifer and Johnbeck’s team conducted two separate clinical studies using newly developed [64Cu]Cu-DOTA-TATE on NET patients. Their findings revealed the outperformance of [64Cu]Cu-DOTA-TATE over [111In]In-DTPA-octreotide [45] and [68Ga]Ga-DOTATOC [46] in terms of spatial resolution, lesion detection rate, and, most importantly, the ability to identify additional lesions.
A recent clinical study of [64Cu]Cu-DOTA-TATE (200 MBq dose) demonstrated that [64Cu]Cu-DOTA-TATE is excellent for lesion detection in neuroendocrine neoplasm patients [47]. In 2020, the Food and Drug Administration (FDA) approved the first 64Cu-labeled PET radiopharmaceuticals, [64Cu]-DOTA-TATE (DetectnetTM), for the localization of somatostatin-targeting receptor (SSTR)-positive NETs in adult patients [48]. Additionally, the radiotracer [67/64Cu]Cu-Sar-TATE was recently entered into multiple clinical trials to diagnose and treat SSTR-positive tumors [49].
In addition to radiolabeled somatostatin-targeting peptides, a series of PSMA ligands have been identified and radiolabeled with Cu radioisotopes for clinical diagnosis and radionuclide therapy applications in PCa [50,51,52]. In 2016, 64Cu-labeled PSMA-617 became the first 64Cu-labeled ligand for PET imaging of PCa patients and was investigated at two nuclear medicine centers (Vienna, Austria, and Bed Berka, Germany) [53]. Even though [68Ga]Ga-PSMA is an excellent tracer to detect PCa and metastatic lesions in the lymph node or bone at low PSA levels [54], the advantage of the lower positron energy of 64Cu (Eβ+avg = 278 keV) vs. 68Ga (Eβ+avg = 829 keV) and the longer half-life (12.7 h) of 64Cu allow its distribution and use as [64Cu]Cu-PSMA-617 at various clinical PET centers with no sophisticated onsite radiotracer production facility [53].
67Cu is one of the most promising radionuclides for radioimmunotherapy (RIT), as its 61.8 h isotopic half-life is well matched with the residence time of a typical Ab on the tumor site. In 1998, DeNardo reported a pilot study of [67Cu]Cu-2IT-BAT-Lym-1 to image and treat chemo-resistive B-cell in non-Hodgkin’s lymphoma while employing favorable SPECT imaging and the remarkable radiotherapeutic effects of 67Cu-labeled 2IT-BAT-Lym-1 [55]. The clinical investigation of Cu radiopharmaceuticals is outlined in Table 2.

4.1.3. Production and Availability

At present, the most common method to produce 64Cu is proton irradiation of enriched 64Ni via a 64Ni(p,n)64Cu nuclear reaction in a small−medium-energy biomedical cyclotron [66]. The main route to produce 67Cu for decades had been via a 68Zn(p,2p)67Cu nuclear reaction that utilizes enriched 68Zn and high-energy proton irradiation (up to 40 MeV), which also coproduces 64Cu [67]. Recently, Mou et al. developed and patented the fabrication of multi-layer targets composed of enriched 70Zn and 68Zn that could maximize 67Cu production yield [68].

4.2. Radioisotopes of Gallium

4.2.1. General Information

Among the many radioisotopes of Gallium (Ga), 66Ga, 67Ga, and 68Ga are predominantly used in medical applications for the radiolabeling of various biomolecules [69]. 67Ga and 68Ga are predominantly used in nuclear medicine for SPECT and PET imaging, respectively. 66Ga ((t1/2 = 9.49 h) is an attractive PET radionuclide with a relatively longer half-life than 68Ga (t1/2 = 67.71 min). Due to its high positron emission energy (Eβ+avg = 1750 keV), though, along with the co-emission of higher gamma rays than 68Ga, 66Ga suffers from poor image resolution and high radiation exposure to workers, limiting its medical application [70].
67Ga is one of the longer-lived Ga radioisotopes, and it decays by EC (100%) with multiple gamma emissions, with the most common gamma energies emitted as 93 keV (39%), 184 keV (21%), and 300 keV (17%) for the SPECT imaging [71]. [67Ga]Ga-citrate is the most popular radiopharmaceutical of 67Ga. For several decades, it has been used in the diagnosis of osteomyelitis and other bone infections [72,73]. To date, [67Ga]Ga-citrate scintigraphy is used worldwide for the diagnosis of lymphomas [74], lung cancer [75,76], and inflammation of the kidneys [77]. The nuclear decay properties of Ga radionuclides are displayed in Table 3.

4.2.2. Clinical Practice

Gallium-68 is one of the earliest radionuclides applied in the early days of PET scans (early 1960s), long before the discovery of [18F]fluorodeoxyglucose (FDG) in 1978 [79]. However, the growth of 68Ga-labeled radiopharmaceuticals in clinical applications began after the commercial launch of next-generation 68Ge/68Ga generators in the early 21st century (mid-2000s) [80,81]. During 2000–2010, various Ga-68-labeled peptide-based radiopharmaceuticals, such as [68Ga]Ga-DOTA-TATE [82], [68Ga]Ga-DOTA-TOC [44,82], and [68Ga]Ga-DOTA-NOC [83], were clinically evaluated in peptide receptor radionuclide therapy (PRRT) to visualize NET-expressing SSTR2. Later, [68Ga]Ga-PSMA-11 (also known as PSMA-HBED, HBED-CC) was investigated for the diagnosis of recurrent PCa, and it received FDA approval in 2020 [84]. Several clinical studies involving 68Ga were recently conducted with its “theranostic twin”, 177Lu, for diagnosis and radionuclide therapy of NETs and PCa. A tremendous growth in the application of [68Ga]Ga-PSMA-11 has occurred for imaging metastatic castration-resistant PCa over other radiotracers. Additionally, there is high demand for its theranostic pair of PSMA, labeled with either beta emitter 177Lu or alpha emitter 225Ac [85,86,87,88]. The clinical investigation of 68Ga radiopharmaceuticals is noted in Table 4.

4.2.3. Production and Availability

Currently, the most convenient method to produce 68Ga is from germanium (Ge) 68 (t1/2~271 d) using 68Ge/68Ga generators [89]. However, the shortage of these generators and on-demand supply of 68Ga have led to the generation of alternative methods of production using, as an example, cyclotrons (12–17 MeV) via the 68Zn(p,n)68Ga nuclear reaction [90]. During 2014–2019, Pandey et al. pioneered cyclotron-mediated 68Ga production using a liquid target to overcome the global shortage of 68Ga [91,92,93]. Besides liquid target-based production, several high-yielding solid target-based production methods, also using cyclotron, have been developed and commercialized to meet the upcoming demands of 68Ga [94,95,96]. On the other hand, the common production of 67Ga through the irradiation of natZn or isotopically enriched 68Zn targets via 68Zn (p,2n)67Ga or 67Zn(p,n)67Ga on cyclotron have been reported [97].
Table 4. Clinical applications of 68Ga-labeled radiopharmaceuticals.
Table 4. Clinical applications of 68Ga-labeled radiopharmaceuticals.
NCT Number ^Disease
[68Ga]Ga-PSMA-11PSMANCT03207139 (Phase II; completed) NCT03982407 (Early Phase I; completed)Latent prostate cancer [98], hepatocellular carcinoma [99]
(Phase I/II; ongoing)
Metastatic castration-resistant prostate cancer [100]
[68Ga]Ga-DOTA-TATE vs. [68Ga]Ga-DOTA-TOCSSTR2NCT04298541 (Phase II; ongoing)Meningioma [101]
[68Ga]Ga-DOTA-TOCSSTRNCT02441062 (Phase II; completed)Neuroendocrine tumors [102]
[68Ga]Ga-FAPi-46FAPINCT04457258 (Early Phase I; ongoing)Sarcoma, recurrent or metastatic, sarcoma [103]
NCT: National clinical trial, NETs: Neuroendocrine tumors, PSMA: Prostate-specific membrane antigen, SSTR2: Somatostatin receptor 2, FAPI: Fibroblast activation protein inhibitor, ^ and data accessed on 15 August 2023.

4.3. Radioisotopes of Zirconium

4.3.1. General Information

Zirconium-89 (89Zr) is a promising radionuclide for the PET imaging of Abs due to its longer physical half-life (78.4 h), which matches with the blood half-life of most full-length Abs (days to weeks) [104]. 89Zr has a relatively short penetration range by emitting low-energy positrons (Eβ+avg = 396 keV), which facilitate high-resolution PET images [104]. However, 89Zr emits an abundance of high-energy γ-rays of 909 keV, adding radiation exposure to medical staff and patients [104]. Table 5 summarizes the decay characteristics of Zr-89.
Table 5. Decay characteristics of Zirconium-89 #.
Table 5. Decay characteristics of Zirconium-89 #.
IsotopeHalf-Life (t1/2)Decay CharacteristicsEnergy
Eβ+avg (keV)
Eγ; keV (Intensity%)
89Zr78.41 hβ+ = 22.3%395.5511 (45.5)
EC = 76.6% 909.2 (99)
# Data on 89Zr are from [105]. Please refer to decay Scheme 1A.

4.3.2. Clinical Practice

In 2006, the first clinical study of [89Zr]Zr-immuno PET was reported, where 89Zr-labeled chimeric mAb U36 localized in all primary tumors and lymph node metastasis of head and neck cancer patients with an accuracy as high as 93% [106]. Presently, the FDA has approved hundreds of mAbs against various biological targets, such as HER2, CD20, epidermal growth factor receptor (EGFR), vascular endothelial growth factor (VEGF), and PSMA, resulting in several [89Zr]Zr-Immuno PET-based clinical oncology trials [107,108]. Currently, [89Zr]Zr-trastuzumab and [89Zr]Zr-pertuzumab are the two common choices for immuno-PET-targeting HER2+ breast cancer. The first-in-human studies using [89Zr]Zr-trastuzumab (37 MBq) and [89Zr]Zr-pertuzumab (74 MBq) on metastatic breast cancer patients were reported in the years 2010 and 2018, respectively [109,110]. Currently, both radiopharmaceuticals are registered in clinical trials.
Additional clinical pilot studies have been published using [89Zr]Zr-immuno-PET probes, such as [89Zr]Zr-bevacizumab targeting VEGF-A expression [111], [89Zr]Zr-rituximab targeting B-lymphocyte antigen (CD20) expression [112], and [89Zr]Zr-cetuximab-targeting EGFR [113], in various tumors. These [89Zr]Zr-immuno-PET probes have been shown to be useful for imaging and/or radionuclide therapy applications. Currently, [89Zr]Zr-bevacizumab is registered in an ongoing clinical trial (National Clinical Trial (NCT) 01894451) [114]. Considering the long blood circulation time of monoclonal Abs (mAbs), alternative Abs and their fragments were developed in the last five years to significantly shorten their retention time in blood and to rapidly clear the unbound fragments from the body [115]. Early examples of Ab fragment application are minibody-based radiopharmaceuticals, such as [89Zr]Zr-Df-IAB2M, which were used to detect PSMA-positive PCa and recurrent cerebral high-grade gliomas [116,117]. In addition to minibody-based radiopharmaceuticals, several preclinical studies reported 89Zr-labeled affibodies, such as [89Zr]Zr-Df-ZEGFR:03115 and [89Zr]Zr-DFO-MAL-Cys-MZ, as targeting EGFR and HER2, respectively [118,119]. To fully evaluate the clinical value of affibodies and Ab fragments, additional clinical studies demonstrating their usefulness are paramount.
Besides Abs, cell labeling with 89Zr has been explored for the imaging of white blood cells and CAR-T cells. Several preclinical studies using [89Zr]Zr-oxine and [89Zr]Zr-Df-aTCRmu-F(ab’)2 were reported to track T cells in glioblastoma and acute myeloid sarcoma, respectively [120,121]. Covalent tethering of [89Zr]Zr-DBN to cells is another highly studied methodology to noninvasively track various cell types with PET. Published reports of this method demonstrate that it offers a robust and reliable approach that could be translated in humans for monitoring cell-based therapies [122,123,124,125]. Table 6 summarizes the clinical applications of 89Zr-based radiopharmaceuticals.

4.3.3. Production and Availability

The production and availability of 89Zr have been improved significantly in the last two decades. Various methods of 89Zr production on solid and liquid targets using cyclotron have evolved over the years, resulting in better and simplified methods of purification and radiolabeling [91,93,126,127,128,129,130,131,132]. The main route of production is proton irradiation of yttrium (Y) via a 89Y(p, n) 89Zr nuclear reaction [126]. At present, 89Zr is routinely produced at various academic institutions for their own use, including Mayo Clinic Rochester, and for supplying other institutions, including the University of Wisconsin, the University of Alabama, and commercial vendors within the United States. Some European and Asian academic institutions also manufacture 89Zr routinely and use it predominantly in preclinical studies. In the last 10 years, several groups have come up with alternative solutions that facilitate the GMP-grade production and formulation of 89Zr. For example, Wooten et al. designed an automated system for routine 89Zr production and purification at high radioactivity quantities, with >99.9% of radionuclidic purity [133]. In terms of purification, Pandey et al. developed a simplified synthesis of hydroxamate resin for trapping of Zr-89 with a trapping efficiency of 93% and its subsequent elution either as oxalate or phosphate in a high elution efficiency (>90%) [134]. Recently, the same group designed a new solid target insert and optimized the thickness of 89Y foil and proton beam energy to improve the production yield of 89Zr (~129 mCi or 4.77GBq) using medium energy cyclotrons [126]. Others in the field have also significantly contributed towards the advancement of Zr-89 production and purification [135,136].
Table 6. Clinical applications of 89Zr-labeled radiopharmaceuticals currently under investigation.
Table 6. Clinical applications of 89Zr-labeled radiopharmaceuticals currently under investigation.
RadiopharmaceuticalsTargetsNCT Number ^Disease
[89Zr]Zr-Df-hJ591PSMANCT01543659 (Phase I/II; ongoing)Prostate cancer [137]
[89Zr]Zr-Df-IAB2MPSMANCT02349022 (Phase II; completed)Prostate cancer [138]
NCT05013099 (Phase IIb; ongoing)
NCT03107663 Phase I; completed)
NCT03802123 (Phase II; completed)
Melanoma [139]
Renal cell
carcinoma [140]
Metastatic solid tumors [141]
[89Zr]Zr-daratumumabCD38NCT03665155 (Phase II; completed)Multiple myeloma [142]
[89Zr]Zr-trastuzumabHER2+NCT01420146 (Phase I; completed)Breast neoplasm [143]
[89Zr]Zr-ss-pertuzumabHER2-NCT04692831 (Phase I; ongoing)Breast carcinoma [144]
[89Zr]Zr-bevacizumabVEGFNCT01894451 (Early Phase I; completed)Inflammatory breast carcinoma [114]
[89Zr]Zr-panitumumabEGFRNCT03733210 (Phase I; completed)Carcinoma of head and neck [145]
[89Zr]Zr-cetuximabEGFRNCT00691548 (Phase I; completed)Stage IV cancer [146]
[89Zr]Zr-girentuximabCarbonic anhydraseNCT03849118 (Phase III; completed)Renal cell carcinoma [147]
[89Zr]Zr-durvalumabPDL-1NCT03853187(Phase II; completed)Non-small cell lung cancer [148]
[89Zr]-DFO-atezolizumabPDL-1NCT04006522 (Phase II; ongoing)Renal cell carcinoma [149]
NCT: National clinical trial, PSMA: Prostate-specific membrane antigen, CD38: Cluster of differentiation 38, HER2: Human epidermal growth factor 2, VEGF: Vascular endothelial growth factor, EGFR: Epidermal growth factor receptor, PDL-1: Programmed cell death ligand-1, ^ and data accessed on 15 August 2023.

4.4. Radioisotopes of Scandium

4.4.1. General Information

Scandium (Sc) has 25 different radioisotopes, but 43Sc, 44Sc, and 47Sc are the commonly explored radionuclides for PET imaging and targeted radionuclide therapy applications [150]. 44Sc and 43Sc are promising PET radionuclides, and they are superior alternatives to 68Ga because of their lower positron energy and almost 3.5-fold longer half-life [150,151]. However, 44Sc also decays via high gamma ray (Eγ = 1157 keV; 99.9% abundance) emission and could give a high radiation exposure dose compared to other competing PET radionuclides [152]. The decay properties of Sc radionuclides are given in Table 7.

4.4.2. Current Clinical Application of Scandium-44

In 2017, the first clinical study of generator-derived 44Sc with [44Sc]Sc-DOTATOC was reported for the imaging of a metastatic neuroendocrine neoplasm at Bed Berka [153]. Recently, [44Sc]-PSMA-617 was also applied for the imaging of PCa patients [154], and it showed performance comparable to [68Ga]Ga-PSMA-617 in terms of tumor uptake and image quality [154]. Given the availability of both imaging (43/44Sc) and therapeutic (47Sc) radionuclides, Sc radiopharmaceuticals are gaining significant interest as an alternative theranostic pair [155].
43Sc is another PET isotope of the Sc family with similar physical characteristics to 44Sc, but it is devoid of high-energy gamma emission and lower positron energy (Eβ+avg = 476 keV), making it a more favorable imaging isotope than 44Sc [150]. However, no preclinical or clinical studies are yet reported with 43Sc-labeled radiopharmaceuticals.
47Sc is a radio theragnostic isotope that emits low-energy β particles (Eβavg = 162 keV) and low-energy γ-radiations (Eγ = 159 keV) [150]. The decay characteristics of 47Sc are like 67Cu (Eβ-avg = 141 keV, Eγ = 184 keV) and 177Lu (Eβavg = 134 keV, Eγ = 113, 208 keV). Recently, a comparative preclinical study with [47Sc]Sc-folate (12.5 MBq), [177Lu]Lu-folate (10 MBq), and [90Y]Y-folate (5 MBq) showed a similar therapeutic response in an ovarian xenograft model [156]. Due to the challenging production routes of 47Sc, though, clinical studies involving 47Sc have yet to evolve [156].

4.4.3. Production and Availability

In 2010, Frank Rosch et al. reported the production of 44Sc (approx.185 MBq) using a 44Ti/44Sc generator for the first time at Bed Berka, Germany [157]. However, the production of the parent radionuclide, 44Ti, and the accessibility of these generators were challenging. Later, in 2015, Van der Meulen et al. reported a cyclotron-based production of 44Sc via proton irradiation (11 MeV) of an enriched 44Ca target, which allowed elution of approximately 2 GBq of 44Sc at the Paul Scherrer Institute (PSI) in Switzerland [158]. Later, Szkliniarz et al. reported several cyclotron-based production routes for emerging 43Sc using either α particles or deuteron beams because the limited availability of high-energy multi-particle cyclotrons restricted the utility of these production routes [159]. Van der Meulen et al. demonstrated the production of 480 MBq of 43Sc using enriched 43CaCO3 and targets via a 43Ca(p,n)43Sc reaction; limited purity of 43Sc was obtained due to the co-produced mixture of 43Sc (66.2%) and 44Sc (33.3%) [160]. 47Sc can be produced using a cyclotron [161], neutron flux reactor [162], or electron linear accelerator [163,164].

4.5. Radioisotopes of Terbium

4.5.1. General Information

Among the various radioisotopes of Terbium (Tb), four (149/152/155/161Tb) are of great interest in nuclear medicine and are commonly referred as a “Swiss army knife” of nuclear medicine [165]. 149Tb has both positron and α-emission properties for both PET and targeted therapy applications [166]. 152Tb is another positron emitter with a relatively longer half-life of 17.5 h that could be utilized for radiolabeling of large biomolecules [166]. The decay characteristics of Tb radionuclides are listed in Table 8.
In 2012, Muller et al. performed the first radiolabeling of albumin-binding folate conjugates (cm09) with 149/152/155/161Tb in an FR-positive tumor xenograft mouse model [167]. The findings demonstrated excellent tumor visualization through PET/CT using [152Tb]Tb-cm09 and SPECT/CT, using both [155Tb]Tb-cm09 and [161Tb]Tb-cm09 probes at 24 h post administration. On the other hand, α therapy version [149Tb]Tb-cm09 and β therapy version [161Tb]Tb-cm09 resulted in significantly delayed tumor growth by 33% and 80%, respectively.

4.5.2. Preclinical and Clinical Applications

149Terbium: 149Tb represents one of the powerful candidates for TAT, which emits short penetrating (~25 µm range) α particles (Eα = 3.97 MeV; Iα = 16.7%) compared to currently employed α emitters [168]. Because 149Tb also decays by positrons (β+) and γ-radiations, 149Tb-labeled radiopharmaceuticals could also be useful for PET and SPECT imaging [168].
In 2004, Beyer et al. demonstrated the first preclinical RIT with [149Tb]Tb-rituximab in a leukemia xenograft mouse model, which resulted in tumor-free survival >120 days among 89% of the [149Tb]Tb-rituximab-treated mice [169]. However, nearly 28% of the residual radioactivity of longer-lived daughter nuclides, 149Eu (t1/2 = 93 d),145Sm (t1/2 = 340 d), and others were retained mainly in the mice bone marrow. Baum et al. demonstrated the first in-man PET/CT study of SSTR-targeted [149Tb]Tb-DOTANOC on a male patient diagnosed with neuroendocrine ileum. The result was an excellent localization of [149Tb]Tb-DOTANOC in this neuroendocrine neoplasm, in addition to multiple lymph nodes, skeletal metastasis, and SSTR-expressing organs [170].
Currently, 149Tb is predominantly produced by ISOLDE/CERN (Switzerland), TRIUMF (Vancouver, Canada), and PNPI (Gatchina, Russia) [171]. More recently, preclinical studies with [149Tb]Tb-DOTANOC and [149Tb]Tb-PSMA-617 were reported in tumor xenograft mouse models of AR42J pancreatic and prostate cancers, respectively [168,172]. Thus far, no clinical study has been reported with 149Tb [168].
152Terbium: 152Tb is a diagnostic radionuclide that decays via positron emission (Eβ+avg = 1142 keV) and multiple gamma radiations, which could lead to high radiation exposure [170]. The relatively long half-life of 152Tb (t1/2 = 17.5 h) allows it to be useful in dosimetry estimation. In fact, 152Tb is an exact diagnostic match for 149Tb and 161Tb, as well as other clinically useful therapeutic radionuclides, like 177Lu, due to their similarities in coordination chemistry and pharmacokinetics.
155Terbium: 155Tb is a suitable SPECT isotope, a promising alternative to the 111In isotope, and it could be useful for dosimetry estimation of β emitters, like 177Lu, 90Y, and 166Ho [173].
161Terbium: 161Tb decays by low-energy (Eβavg = 154 keV) (β) emission, having a short tissue penetration (0.29 mm) range and a long half-life (t1/2) of 6.8 d [174]. The decay characteristics and half-life of 161Tb are like 177Lu (Eβavg = 134 keV, t1/2 = 6.7d) [174], although 161Tb also emits a substantial number of auger electrons, which could be advantageous for therapeutic applications. However, the clinical superiority of 161Tb over 77Lu is yet to be established [175,176,177]. In addition to radionuclide therapy, 161Tb also emits gamma photons enabling SPECT imaging [174]. Recently, Baum et al. demonstrated the first-in-human SPECT imaging using [161Tb]Tb-DOTATOC in patients with paraganglioma and NETs and showed high-quality images and visualization of hepatic metastasis as well as multiple osteoblastic skeletal metastasis in patients [178].
The main constraint to the wider application of Tb isotopes is their availability: there are insufficient production quantities. The production of Tb isotopes requires expensive enriched targets and accelerator-based isotope separation on-line technology (ISOLDE), which is not widely available [166]. Table 9 summarizes the clinical investigation of Tb radionuclides.

4.5.3. Production and Availability

In 2012, Muller et al. reported on the production of 149/152/155Tb in a range of ~6–15 MBq activity through a high-energy proton-induced spallation of tantalum foil targets, followed by dissolution and isotope separation [167]. Such a high-energy proton accelerator facility and mass separation technology (ISOLDE) are limited to a few centers worldwide, including CERN, Switzerland. Lately, CERN-MEDICIS (Medical isotopes collected from ISOLDE) technology was developed, which allowed for the production of 38 GBq of 149Tb, 37 GBq of 152Tb, and 5.3 GBq of 155Tb [166]. 161Tb (up to 15 GBq) can be produced in a neutron flux reactor using 160Gd targets, as proposed by Lehenberger et al. at PSI, Switzerland [181]. Interestingly, the production concept and the cost of 161Tb is like a non-carrier added 177Lu [181].

4.6. Radioisotopes of Zinc

4.6.1. General Information

Zinc (Zn) exists in three positron-emitting isotopes (62/63/65Zn) that have the potential to be used as PET biomarkers of zinc trafficking in various pathological conditions [182]. Among them, 62Zn has limited use because it decays to another positron-emitting isotope, 62Cu (β+ = 98%; t1/2 = 9.7 min), which could confound the image interpretation of PET scans [182]. Nevertheless, 62Zn has been used preclinically to image zinc transport in pancreatic exocrine function [183].
Among the Zn PET isotopes, 65Zn has the longest half-life (t1/2 = 243.9 d), making it unsuitable for diagnostic imaging because it will cause high radiation exposure to patients over time [182]. 63Zn has a favorable decay characteristic (β+ = 93%; t1/2 = 38.47 min) for diagnostic imaging and pharmacokinetic studies [184,185]. The decay properties of Zn radionuclides are given in Table 10.

4.6.2. Clinical Applications

In 2016, DeGrado et al. conducted the first-in-human PET imaging study of [63Zn]Zn-citrate on Alzheimer’s disease patients [185]. Although low uptake of [63Zn]Zn-citrate was seen in the brain (SUV ~0.4) compared to other organs, like the liver, pancreas, kidney, and gastrointestinal tract, it was sufficient to study 63Zn clearance kinetics on a regional basis in those patients. The regions with slower 63Zn clearance corresponded to the regions of known amyloid-β pathology on [11C]C-PiB PET scans and also the regions of lower uptake on [18F]FDG-PET scans [185]. Further imaging studies are warranted, though, to study zinc homeostasis in persons with Alzheimer’s disease.

4.6.3. Production and Availability

In 2014, DeGrado et al. developed a cyclotron-based production of 63Zn via a 63Cu(p,n)63Zn nuclear reaction using a liquid target by irradiating an isotopically enriched solution of [63Cu]Cu-nitrate [184]. 63Zn was produced with a specific activity of 41.2 + 18.1 MBq/µg (uncorrected) and radionuclidic purity of 99.9% using 1.23 M of [63Cu]-copper nitrate.

5. SPECT Probes

5.1. Technetium-99m

5.1.1. General Information

Technetium-99m (99mTc) is the most widely used medical isotope in nuclear medicine, accounting for more than 80% of all nuclear medicine procedures, including myocardial perfusion imaging, cancer, and infection imaging [186]. 99mTc-based agents are a favored choice for cardiac imaging in the U.S [187]. 99mTc mainly disintegrates into its other isomeric 99Tc (which is radioactive) with the release of low-energy monochromatic gamma rays (140.5 keV, 98.6%) that can be detected by any sensitive gamma cameras [188]. Despite the advent of superior PET technology and the prevalence of CT or MRI over nuclear medicine, 99mTc-based radiopharmaceuticals have been continuously supplied in hospitals during routine clinical examinations [188]. The advantages behind them are (i) a short/sufficient half-life of 6 h, which offers minimum radiation exposure to patients, (ii) instant kit-based labeling and formulations due to rich coordination chemistry of Tc (multiple oxidation states), (iii) availability of transportable generators (99Mo/99mTc) for production, and (iv) cost-effective SPECT gamma cameras compared to expensive PET technology. These points have solidified the continuous application of 99mTc-labeled radiopharmaceuticals [188,189]. The nuclear decay characteristics of 99mTc are given in Table 11.

5.1.2. Clinical Applications

Among the various clinical applications of 99mTc-labeled radiopharmaceuticals, [99mTc]Tc-HYNIC-TOC (Tektrotyd) is commercially available for the imaging of metastatic NETs [190]. A recent comparative study of [68Ga]Ga-DOATATE and [99mTc]Tc-HYNIC-TOC (99mTc-octreotide) on NET patients showed the superiority of [68Ga]Ga-DOATATE over [99mTc]Tc-HYNIC-TOC in terms of sensitivity and specificity [191]. However, it is reasonable to re-evaluate the performance of 99mTc-radiopharmaceuticals using ultra-fast SPECT scanners that may increase the image resolution up to twofold [192]. Additionally, [99mTc]Tc-MIP1404 and [99mTc]Tc-MIP-1405 are the first [99mTc]Tc-labeled PSMA ligands applied in humans [193]. Although both agents can visualize PSMA tumors and metastatic lymph node/bone lesions, [99mTc]Tc-MIP1404 (also known as Tc-Trofolastat) is advantageous over [99mTc]Tc-MIP-1405 to detect PCa at early stages of the disease, and it is currently registered in a phase 3 clinical trial (NCT02615067) [194]. In 2016, another promising PSMA-based SPECT agent [99mTc]Tc-PSMA-Investigation & Surgery was applied for first-in-human radio-guided surgery (RSG) [195]. The clinical applications of 99mTc radiopharmaceuticals are summarized in Table 12.

5.1.3. Production and Availability

99mTc is a radioactive decay product of 99Mo (t1/2 = 66h), which is traditionally made in a large nuclear reactor via fission of high-enriched uranium targets (235U) [189]. The production of 99mTc in the form of pertechnetate [99mTc]TcO4 from the parent 99Mo was achieved using the commercially available and transportable 99Mo/99mTc generators in nuclear medicine for the preparation of almost all of the 99mTc-based radiopharmaceuticals. Until 2011, the global requirement for 99Mo was fulfilled by seven nuclear research reactors. The mandatory shutdowns of these reactors for maintenance or due to breakdowns stopped the global supply in 2009, 2012, and 2013 [189]. To overcome such an unavoidable global crunch in the supply of 99Mo, several research efforts were initiated, including the use of linear accelerators and cyclotrons, which utilize electron beam and proton irradiation of solid 100Mo targets, respectively [205,206].

5.2. Indium-111

5.2.1. General Information

Indium-111 (111In; t1/2 = 2.8 d) is a SPECT isotope that decays by EC (100%) and low- energy γ-emission (171 keV, 245 keV) [207]. The decay characteristics are summarized in Table 13. Over the decades, 111In has been used as the reference standard for SPECT-immuno imaging of Abs [207]. 110mIn is a PET radioisotope of In with a short half-life (69 min), and it is suitable for tracking short peptides (e.g., octreotide) having faster kinetics [208].

5.2.2. Clinical Practice

In mid-1978, McAffee and Thakur introduced a radiotracer, [111In]In-oxine, which could be used to radiolabel leukocytes (white blood cells (WBC)) for the scintigraphic detection of focal infections [209]. In 1985, the FDA approved [111In]In-oxine-tagged WBC scans for clinical imaging of inflammatory disease [210]. The reported sensitivity and specificity of these [111In]In-WBC scans ranged from 60–100% to 69–92%, respectively, in detecting osteomyelitis, vascular grafts infection, bone infections, etc. [211]. Other than cell labeling, 111In was also used in radiolabeling of various peptides, proteins, Abs, and drugs. For example, [111In]In-capromab pendetide (ProstaScint®) was FDA-approved for immuno-SPECT imaging of PCa [212]; however, the poor tumor-to-background signals limited its routine clinical use [212]. Later, another promising PSMA immuno-SPECT tracer, [111In]In-J591 (PSMA-Ab), was developed, and the first clinical trial was reported in 2005 [213]. Clinical trials of [111In]In-J591 are underway and associated with the dosimetric projections of RIT with [90Y]Y-J591 [214]. Furthermore, in 2018, Heckman et al. demonstrated the first-in-man study using the novel SPECT tracer [111In]In-DOTA-girentuximab for intraoperative guidance of renal cell carcinoma resection in patients [215]. Table 14 summarizes the clinical application of 111In-labeled radiopharmaceuticals.

5.2.3. Production and Availability

The most common production route of 111In in a high yield (222 ± 5 MBq/µA.h) is proton irradiation (21 MeV) of enriched 112Cd target via a 112Cd (p,2n) 111In nuclear reaction using a cyclotron [216].
Table 14. Clinical applications of 111In-labeled radiopharmaceuticals.
Table 14. Clinical applications of 111In-labeled radiopharmaceuticals.
RadiopharmaceuticalsTargetsNCT Number ^Disease
[111In]In-CP04CCK2R/gastrinNCT03246659 (Phase I; completed)Thyroid carcinoma [217]
[111In]In-Ch806gp140, IL-13RA2NCT00291447 (Phase I; completed)Neoplasm [218]
[111In]In-capromab pendetide (ProstaScint®)PSMANCT00992745 (Phase I; completed)Prostate cancer [219]
[111In]In-PSMA (I&T)PSMANCT04300673 (Phase I ongoing)Prostate cancer [220]
[111In]In-DOTA-GirentuximabCarbonic anhydrase-IXNCT02497599 (Phase I; status unknown)Renal cell carcinoma [221]
[111In]In-labeled leukocytesLeukocytesNCT00026897 (Phase II; completed)Neoplasm [222]
NCT: National clinical trial, CCK2R/gastrin: Cholecystokinin receptor, gp140: glycoprotein 140, PSMA: Prostate-specific membrane antigen, ^ and data accessed on August 15, 2023.

6. Beta Minus Emitter

6.1. Yttrium-90

6.1.1. General Information

Yttrium-90 (90Y) is a pure high-energy β emitter (Eβmax = 2284 keV, Eβavg = 933 keV), which decays to stable Zr-90 with no accompanying gamma emissions [223] (Table 15). Y-90 has a longer tissue penetration depth of up to 11.8 mm [223]. To date, Y-90 has been radiolabeled with tumor-targeting Abs [224], SSTR-targeting peptides [225], and resins/glass microspheres to treat a variety of tumors [226].

6.1.2. Clinical Application of 90Y

The FDA has approved two types of 90Y microspheres, TheraSphereTM (glass microspheres) and SIR-spheres® (resin microspheres), to treat unresectable hepatocellular carcinoma and colorectal metastasis, respectively [227,228].
These 90Y-microspheres have been used in therapies based on the concept of “radioembolization” (also known as selective internal radiation therapy); it is a promising catheter-based liver-directed therapy approved by the FDA for patients with primary/metastatic liver tumors. It was found that the antitumor effect of 90Y-microspheres (glass microspheres, also known as ThersphereTM) are related to beta radiations rather than embolization and therefore proven safer/successful for advanced-stage liver cancer [227]. The recent phase III trials of radioembolization of 90Y-resin microspheres in patients with HCC demonstrated significantly higher tumor response with respect to standard first-line treatment with Sorafenib. However, these results did not meet the primary endpoint, such as overall survival or the patient’s quality of life. Several Asian guidelines recommend 90Y-resin microspheres for HCC treatment based on certain considerations, such as patient selection, treatment planning using accurate dosimetry pre/post-radioembolization, and technical aspects [229,230,231,232].
In 2002, the FDA approved the first anti-CD20 radioimmunoconjugate [90Y]Y-Ibritumomab tiuxetan (ZevalinTM) for the treatment of advanced B-cell lymphoma as a first line of treatment for rituximab-relapsed or refractory low-grade lymphomas; the overall response rate has ranged from 74% to 82% [233]. Despite the demonstrated immunotherapy efficacy of ZevalinTM, it failed commercially due to the underutilized practice by hematologist–oncologists for logistic and economic reasons [234]. In addition, other competitive RIT drugs, such as rituximab (anti-CD20) and second-generation mAbs, undoubtedly contributed to the limited sale of ZevalinTM [235,236].
The development of second-generation mAbs, particularly bispecific Abs (e.g., biotin, IgG-single chain variable fragment), have been utilized in an alternative approach called multi-step pre-targeted RIT to enhance the therapeutic efficacy and to diminish its toxicities [237]. Based on PRIT technology, [90Y]Y-DOTA-biotin was developed, which makes a strong conjugate with Abs (streptavidin, avidin) present on the tumor. In 1999, Paganelli et al. published the first clinical preliminary results of [90Y]Y-DOTA-biotin for the treatment of high-grade gliomas (n = 48) based on biotin–streptavidin chemistry and showed tumor reduction (>25–100%) in 25% of patients; in 16% of these, the response lasted for at least a year [238]. In 2000, a phase II clinical trial of [90Y]Y-DOTA-biotin was reported in patients with metastatic colon cancer [239]. Despite evaluating the feasibility, safety, and efficacy of [90Y]Y-DOTA-biotin, the immunogenicity of these types of pre-targeting agents have not been addressed, which in turn caused the clinical trials to end in 2005 [240].
Paganelli et al. developed an innovative therapeutic approach called “Intra-operative avidination for radionuclide therapy” (IART®) that relies on a biotin–avidin binding system [241]. A phase II study of IART® in 2010 using [90Y]Y-DOTA-biotin on breast cancer patients demonstrated its potential use immediately after breast resection, thereby shortening the time course of external beam radiotherapy [241]. In the past decade, several peptide-based 90Y-tracers were developed for PRRT, and they are currently under clinical trial. Table 16 summarizes the clinical application of 90Y radiopharmaceuticals.

6.1.3. Production and Availability

90Y can be produced from the 90Sr/90Y generator, where the parent isotope is 90Sr (t1/2 = 29 y), and it can be generated as a by-product in large quantities in U-based nuclear reactions [242]. Commercial availability and the steady supply of Y-90 are advantageous in conducting Y-90-based clinical trials.
Table 16. Clinical applications of 90Y-labeled radiopharmaceuticals.
Table 16. Clinical applications of 90Y-labeled radiopharmaceuticals.
RadiopharmaceuticalsTargetNCT Number ^Disease
[90Y]Y-cG250-NCT00199875 (Phase I; completed)Renal and kidney cancer [243]
[90Y]Y-hM5ACEANCT00645060 (Phase I; completed) NCT01205022 (Phase I; completed)Unspecified adult solid tumor [244]
Colon and rectal cancer [245]
[90Y]Y-hPAM4MUC1NCT00603863 (Phase I/II; completed)Pancreatic [246]
[90Y]Y-DOTATOCSSTRNCT05568017 (Phase II; ongoing)Pancreatic neuroendocrine tumor [247]
[90Y]Y-edotreotideSSTRNCT00006368 (Phase I; completed)Brain, breast, and lung cancer, lymphoma, melanoma, neoplastic syndrome [248]
[90Y]Y-resin microspheres (SIR-spheres®)-NCT01482442 (Phase III; completed)Liver carcinoma [249]
[90Y]Y- Ibritumomab Tiuxetan (ZevalinTM)CD20 + B cellsNCT01446562 (Phase II; completed)Follicular lymphoma [250]
NCT: National clinical trial, CEA: Carcinoembryonic antigen, MUC1: Mucin 1, SSTR: Somatostatin receptors, CD20: Cluster of differentiation 20, ^ and data accessed on 15 August 2023.

6.2. Radioisotopes of Rhenium

6.2.1. General Information

Among several radioisotopes of rhenium (Re), 186Re and 188Re are recognized for their therapeutic potential, and they were used to develop various therapeutic radiopharmaceuticals. In addition to beta emission,186Re and 188Re also emit low-abundant γ-rays of 137 keV and 155 keV, respectively (Table 17), that permit scintigraphic monitoring and dosimetry calculations via SPECT imaging [251].
Given the two distinct tissue penetration ranges of 188Re (11 mm) and 186Re (4.5 mm), they can be selectively applied for treating large-sized tumors and small- or mid-sized tumors, respectively [251]. Moreover, to better understand the biodistribution, 99mTc represents a diagnostic match for 186/188Re radioisotopes, as both Re and Tc exhibit similar chemical properties [251]. However, 99mTc- and 188Re-labeled radiotracers do not always show the same in vivo biodistribution [251].

6.2.2. Clinical Applications of Rhenium Radioisotopes

188Re-labeled therapeutic radiopharmaceuticals have been investigated in multiple clinical trials involving primary tumors, bone metastasis, rheumatoid arthritis, and intracoronary β-brachytherapy [252]. In 1998, Maxon et al. evaluated phosphonate-based radiotracer [188Re]Re-HEDP for bone pain palliation [253]. Bone pain is a major issue in ~50% of women with breast cancer and 80% of men with PCa. A phase III trial comparing [188Re]Re-HEDP with a well-known bone-targeting agent [223Ra]RaCl2 is ongoing (NCT03458559). The primary objective of this study is to compare the overall survival in patients with PCa metastatic to bone after treatment with [188Re]Re-HEDP and [223Ra]RaCl2. Several Ab fragments have been radiolabeled with 186/188Re for RIT. These include alemtuzumab (anti-CD66) in leukemia [254], rituximab (anti-CD20) in lymphoma [255], MN-14 (ant-CEA) in gastrointestinal cancer [256], and bivatuzumab in head and neck cancers [257]. Among them, the evaluation of [186Re]Re-bivatuzumab in a variety of diseases (NCT02204033) as a phase I clinical trial has been completed. However, the results are not yet published. Recently, 188Re-colloids-based brachytherapy kit (Rhenium-SCT®) became commercially available to treat basal cell carcinoma or squamous cell carcinoma, particularly to the face and neck, where surgery and radiotherapy are either not possible or refused by patients (NCT05135052) [258]. Several preliminary clinical reports have demonstrated that this innovative epidermal therapy is effective in 98% of melanoma patients even after a single application [259]. The clinical investigations of Re radiopharmaceuticals are summarized in Table 18.

6.2.3. Production and Availability

188Re is routinely produced in high specific activity by a 188W/188Re generator, like the 99mTc generator [260]. On other hand, 186Re is most commonly produced in apparent specific activity of 111–148 GBq/mg at the Missouri Research Nuclear Reactor [261].
Table 18. Clinical applications of 188Re-labeled radiopharmaceuticals.
Table 18. Clinical applications of 188Re-labeled radiopharmaceuticals.
RadiopharmaceuticalsTargetsNCT Number ^Disease
[188Re]Re-HEDP vs. [223Ra]RaCl2Bone metastasisNCT03458559 (Phase III; ongoing)Prostate cancer metastatic to bone [262]
[186Re]Re-labeled bivatuzumabVEGF-ANCT02204046 (Phase I; completed), NCT02204059 (Phase I; completed), NCT02204033 (Phase I; completed)Adenocarcinoma [263]
Non-small cell lung carcinoma [264]
Head and neck neoplasm [265]
Rhenium-SCT®Skin lesionsNCT05135052 (Phase not applicable; ongoing)Non-melanoma skin cancer [258]
[186Re]Re-nanoliposome-NCT01906385 (Phase I/II; ongoing)Glioma [266]
NCT: National clinical trial, VEGF-A: Vascular Endothelial Growth Factor Receptors-A, ^ and data accessed on 15 August 2023.

6.3. Holomium-166

166Ho is not only a β emitter but also a gamma emitter; it is one of the lanthanide radionuclides that can be imaged using SPECT and MRI [267,268]. 166Ho is a theranostic radionuclide with favorable physical decay characteristics, including a sufficient half-life of 26.6 h, an average emission energy of (Eβav) of 670 keV, a soft tissue penetration range of 8.7 mm, and a low-energy γ-emission (80.5 keV, 6%) for SPECT imaging [267,268]. Being a lanthanide with its paramagnetic properties, 166Ho-labeled drugs enable the visualization and quantification of the biodistribution of drugs in the tumor tissues by means of SPECT and MRI [268]. In 1991, Murphy et al. first investigated the potential possibility of 166Ho microspheres for the internal radiation therapy of hepatic tumors in rabbits [269]. In 2010, Smith et al. investigated the first 166Ho-based liver radioembolization, which was followed by growing interest in this treatment possibility, as evidenced by the increasing number of publications in the last few years [268]. In terms of clinical applications, 166Ho-microspheres serve as an alternative to existing 90Y microspheres to treat liver tumors, with potential advantages of the shorter half-life of 166Ho (t1/2 = 26.6 h) compared to 90Y (t1/2 = 64 h) along with its quantification by MRI [268]. Additional information on 166Ho- radiopharmaceuticals have been discussed in a recent review by Klaassen et al. [270]; therefore, we have kept the discussion extremely short.

6.4. Lutetium-177

6.4.1. General Information

177Lu is currently the most important and highly valuable theranostic β/γ-emitting radionuclide in nuclear medicine across the globe [271]. 177Lu has a long half-life (t1/2 = 6.7d) and decays to 177Hf by emitting medium-energy cytotoxic β particles, with the most abundant β particles (78%) having a maximum energy of 0.497 MeV (Table 19) [271]. Furthermore, the co-emission of γ-photons (112.9 keV, 208.5 keV) enables the visualization and quantification (dosimetry) of the biodistribution of 177Lu- radiopharmaceuticals using SPECT [271].

6.4.2. Clinical Applications

Since 2000, 177Lu-labeled somatostatin analogues have been utilized in PRRT for the treatment of inoperable or metastatic NETs [272]. 177Lu-labeled somatostatin has six- to seven-fold higher affinity for SSTR2 compared with its 90Y-loaded counterpart [272]. Several preclinical and clinical studies have been conducted on the therapeutic effectiveness of 177Lu-based radiopharmaceuticals in last two decades [273]. In 2005, the first-in-human proof-of-concept study was published on endoradiotherapy with [177Lu]Lu-PSMA-I & T, which was found to be promising in patients with castration-resistant and metastatic prostate cancers [274].
In 2017, the results of a clinical phase 3 trial (NETTER-1) involving 229 patients randomized to either PRRT using [177Lu]Lu-DOTATATE (7.4 GBq every 8 weeks) or a long-acting release (LAR) formulation of octreotide (control groups) to treat patients with midgut NET were released [275,276]. The groups receiving [177Lu]Lu-DOTATATE had a significantly higher response rate (18%) and longer progression-free survival (65.2%) at 20 months compared to the controls, with 10.8 and 3%, respectively. [177Lu]Lu-DOTATATE treatment yielded a clinically significant improvement in progression-free survival as a primary end point as well as an improvement in the median survival of 11.7 months [276]. Overall, the treatment was well tolerated with grade 3 or 4 adverse events, which were similar in both the groups. No evidence of renal toxicities was observed among patients in the [177Lu]Lu-DOTATATE groups [275,276]. In 2018, the U.S. Food and Drug Administration (FDA) and the European Medicines Agency (EMA) approved [177Lu]Lu-DOTATATE (Lutathera ®; Novartis company) for mid gut NET. In the same year, [177Lu]Lu-PSMA-617 was proposed for the treatment of metastatic castration-resistant prostate cancer (mCRPC). The results of a phase 2 trial (TheraP) demonstrated a significant decline (>50%) in PSA in the groups treated with [177Lu]Lu-PSMA-617 compared to the standard treatment using Carbazitaxel, which eventually led to FDA and EMA approvals under the name of Pluvicto®(Novartis). The clinical use of 177Lu-radiopharmaceuticals has been increased in the past few years, including [177Lu]Lu-FAPI-46 [277,278] and combination therapy with 90Y-labeled peptides and chemotherapy. Several clinical trials of 177Lu-based radio theranostics are underway, as listed in Table 20.

6.4.3. Production and Availability

There are two common independent ways to produce large-scale 177Lu in nuclear reactors. The first is a direct production route (also known as carrier added or c.a.) based on neutron irradiation of 176Lu via 176Lu (n, γ) 177Lu nuclear reaction in medium–high-energy reactors [271,288]. The second approach is an indirect production route (also known as non-carrier added or n.c.a) based on neutron irradiation of 176Yb target via 176Yb (n, γ) 177Yb →177Lu in high-energy flux reactors [288]. The advantage of the direct production route is that it can create large quantities of 177Lu (740–1110 GBq) using 176Lu; however, the major concern is the co-emission of small amounts of long-lived radioactive impurity of 177mLu along with “useful” 177Lu. Additionally, only a part of the target matrix (or carrier) of 176Lu is converted into the desired 177Lu, which cannot be chemically isolated as they are the isotopes of the same element; this therefore decreases its specific activity [288].
On the other hand, the indirect approach using highly enriched 176Yb (>98%) produces high specific activity (>2.96 TBq/mg) non-carrier-added 177Lu; however, this process requires a suitable method for the radiochemical separation of 177Lu from 176Yb, which is quite challenging, especially in large-scale or industrial settings, to meet the surging demand [271,288]. 177Lu can also be produced in cyclotron using deuteron beams (<6 MeV); however, this is less explored due to the low production yield [288].

7. Alpha-Particle-Emitting Radiopharmaceuticals

Alpha radiations are better suited for the treatment of small metastasis due to their short tissue penetration range and high LET per micrometer of tissue compared to β-emitting radionuclide via double strand DNA breaks in cancerous cells, while sparing nearby healthy tissues [21]. However, due to the early stages of development of alpha-targeted radionuclide therapy, most clinical trials continue to use beta-emitting radionuclide therapy rather than alpha-emitting radionuclide therapy.

7.1. Radioisotopes of Bismuth

7.1.1. General Information

Two promising medically relevant isotopes of bismuth (Bi) with mixed α/β emission properties are 212Bi and 213Bi [289]. 212Bi undergoes β decay (64%) to 212Po (α-emitter) and α-decay (36%) to 208Tl (β emitter). Both daughters of 212Bi (212Po and 208Tl) further decay to the stable 208Pb [289]. Moreover, the emission of high-energy γ-rays through the decay of 208Tl (2.6 MeV) necessitates appropriate shielding to avoid radiation exposure, making it a less favorable choice over 213Bi [289].
213Bi is considered a magic bullet in targeted radionuclide therapy. The isotope predominantly undergoes β decay (97.8%) to the pure α-emitter 213Po, whereas the remaining 213Bi (2.2%) undergoes α- decay to beta-emitter 209Tl [289]. Both of these daughter nuclei (213Po, 209Tl) decay to 209Pb, which further decays to long-lived 209Bi (essentially stable) [289]. In addition, 213Bi also emits γ-radiation (440 keV) that can be employed for SPECT imaging [289]. Overall, each 213Bi decay delivers only one α particle (5.9–8.4 MeV) [289]. The nuclear decay properties of Bi radionuclides are given in Table 21.

7.1.2. Clinical Applications of 213Bismuth

In 2002, Joseph et al. reported the first proof-of-concept phase I study demonstrating the anti-leukemic effect of 213Bi conjugated with anti-leukemia Ab HuM195 (Lintuzumab) to treat leukemia patients [290]. In a subsequent clinical study (phase I/II) in 2010, complete remission was seen in acute myeloid leukemia patients with sequential administration of [213Bi]Bi-HuM195 (37 MBq/Kg) and the chemotherapy drug cytarabine (Table 22) [291]. The promising clinical results with [212Bi]Bi-mAb-TAT initiated its use to treat other cancers, including melanoma, NETs, and glioma [292,293].
In the last two decades, research efforts have facilitated the development of 213Bi-based peptide conjugates for PRRT study. In 2014, Kratochwil et al. reported the first and only radiopeptide therapy with [213Bi]Bi-DOTATOC on NET patients, which was refractory to β therapy with 90Y/177Lu-DOTATOC [294]. The results indicated that TAT could induce considerable and long-lasting remission in both the primary tumor and liver metastases [294]. Another tracer, [213Bi]Bi-PSMA-617, was reported in metastatic castration-resistant PCa patients [295]. The remarkable drop in prostate-specific antigen levels from 237 µg/L to 43 µg/L after [213Bi]Bi-PSMA-617 treatment showed the great potential of TAT using [213Bi]Bi-PSMA-617 over conventional β radionuclide therapy. In addition, TAT may be able to break the radioresistant effect of β emitters [295]. In the past few years, different clinical trials have used 213Bi-carrying radiopharmaceuticals for the treatment of various diseases. Although the outcomes were encouraging, further investigations are needed to ensure its safety and efficacy in the clinic.
Table 21. Decay characteristics of radioisotopes of Bismuth #.
Table 21. Decay characteristics of radioisotopes of Bismuth #.
IsotopeHalf-Life (t1/2)Decay CharacteristicsParent Nuclides and Their Daughter NuclidesEnergies (MeV)Eγ; keV (Intensity%)
Eα (MeV)Eβ (MeV)
212Bi61 minβ = 64%
α = 36%
208Pb (stable)
212Bi-727.3 (6.6)
208Tl-277.4 (6.3), 510.8 (22.6), 583.2 (84.5), 763 (1.8), 860.6 (12.4), 2614.5 (99.2)
213Bi45.6 minβ = 98%
α = 2%
209Bi (essentially stable)
5.9 (213Bi)
8.4 (213Po)
213Bi-440 (25.9)
# Data on 212Bi are from [296] and data on 213Bi are from [297]. Please refer to Scheme 2.

7.1.3. Production and Availability

Many α-emitter radionuclides are produced from naturally occurring heavy α radionuclides, including U, radium (Ra), and actinium (Ac). The clinical amount of 213Bi is obtained from its parent radionuclide 225Ac (t1/2 = 9.9 d) as a 225Ac/213Bi generator [298]. The parent isotope 225Ac is obtained from the decay of 229Th (t1/2 = 7317 y), which in turn originates from a decay chain of fissile materials of 233U [298]. The relatively long half-life of the parent radionuclide 225Ac allows shipment of the 225Ac/213Bi generator to any radiopharmaceutical facility located even long distances away and permits in-house generation of 213Bi for radiolabeling purposes over weeks to months. However, the limited global production of 229Th and the concern for the non-proliferation of the fissile product of 233U restricted the commercial supply of 225Ac stocks to produce 213Bi-labeled radiopharmaceuticals [293]. An alternate route to producing 225Ac is using proton irradiation of 226Ra targets via 226Ra (p,2n) 225Ac in a cyclotron; still, the presence of hazardous 222Rn poses serious limitations in clinical translation and waste disposal [293].
Table 22. Clinical applications of 213Bi-labeled radiopharmaceuticals.
Table 22. Clinical applications of 213Bi-labeled radiopharmaceuticals.
RadiopharmaceuticalsTargetsNCT Number ^Disease
[213Bi]Bi-M195CD33NCT00014495 (Phase I/II completed)Leukemia, myelodysplastic syndromes [299]
NCT: National clinical trial, ^ and data accessed on 15 August 2023.

7.2. Actinium-225

7.2.1. General Information

225Ac is one of the promising therapeutic isotopes for α-RIT of cancer. It decays to six principal intermediate radionuclide progenies (221Fr, 217At, 213Bi, 213Po, 209Tl, 209Pb) before reaching the stable 209Bi [300]. Overall, 225Ac decay (t1/2 = 9.9 d) contributes to the emission of four α-, three β, and two principal γ-emissions (218 keV; 221Fr, 440 keV; 213Bi), from which recognizable 225Ac results as a “nanogenerator.” 225Ac is also considered an in vivo generator of 213Bi and an alternative to 213Bi-based TAT, presumably because of the four α- emissions and its longer half-life compared to 213Bi (t1/2 = 45.6 min) [300]. The decay characteristics of Bi radionuclides are given in Table 23.
225Ac-based radiopharmaceuticals are prone to the redistribution of daughter progenies, particularly 213Bi, which can induce renal toxicity and dose-limiting toxicity to other organs [300]. Moreover, dosimetry is essential using an isotope with a similar half-life and chelation chemistry to 225Ac (e.g., Ln3+) to track the biodistribution of 225Ac accurately. A handful of clinical trials of 225Ac are underway.

7.2.2. Clinical Applications of Actinium-225

In 2011, the first clinical study of α therapy was reported showing the anti-leukemic effect of [225Ac]-lintuzumab in acute myeloid leukemia patients (>60 y) [301]. Motivated by the initial findings, several clinical trials (phase I/II), including a dose-escalation study of [225Ac]Ac-lintuzumab combined with low-dose chemotherapeutic drugs (e.g., mitoxantrone, cladribine), have been initiated (NCT03867682 [258]).
By 2018, a multicenter phase I study using [225Ac]Ac-FPI-1434 (NCT03746431) was designed to treat solid tumors from non-cell lung, prostate, and breast carcinomas [302]. Recently, a clinical study reported by Kratochwil et al. demonstrated the remarkable anti-tumor effect of [225Ac]Ac-PSMA-617 (100 kBq/kg) in 81% of metastatic castration-resistant PCa patients [303]. Additional clinical trials are warranted to further investigate the anti-tumor potential of [225Ac]Ac-PSMA-617 TAT in men with prostate cancer (NCT04597411). The clinical investigation of 225Ac radiopharmaceuticals is summarized in Table 24.

7.2.3. Production and Availability

Currently, the clinical supply of 225Ac is produced from 229Th generators (t1/2 = 7340 y), which are obtained from the parent 233U (t1/2 = 160,000y) [300]. 229Th generators are available at the Oak Ridge National Laboratory USA, the Institute of Transuranium Elements, Germany, and the Institute of Physics and Power, Russia [300]. However, as of 2008, the approximate total worldwide production of 225Ac accounts for only 68 GBq/year, which can support only several hundred patients per year. Therefore, large-scale production of 225Ac is needed. Alternative production routes are being explored, including proton irradiation of 226Ra targets, which could produce sufficient quantities of 225Ac due to the relatively high reaction cross-section; however, the handling of 226Ra (t1/2 = 1600 y) is challenging [300].
To date, the accelerator-based production route involves high-energy proton irradiation (>100 MeV) of natural thorium (232Th), and it could serve as another potential path for the future production of 225Ac. This method may yield twenty times greater quantities of 225Ac than the current annual production worldwide [310].

7.3. Radioisotopes of Lead

7.3.1. General Information

Lead (212Pb; t1/2 = 10.6 h) is a β-emitting radionuclide that decays to 212Bi (t1/2 = 61 min), which decays by mixed α/β- particle emission [311]. Importantly, 212Pb also emits imageable γ-radiation (238.6 keV) that has the potential to image 212Pb-labeled radiopharmaceuticals directly via SPECT imaging (Table 25). Moreover, 203Pb is a γ-emitting analogue of 212Pb, and it is considered an ideal SPECT imaging isotope for the estimation of an accurate dosimetry for 212Pb-labeled therapeutic radiopharmaceuticals [311].

7.3.2. Clinical Practice

During 2014–2018, Meredith et al. performed several clinical studies using therapeutic [212Pb]Pb-TCMC-trastuzumab in HER2 expressing malignancy, with promising outcomes, including improved safety, tolerability, and therapeutic efficacy [313,314,315]. Delpassand et al. investigated [212Pb]Pb-DOTAMTATE (Alpha MedixTM) for the treatment of inoperable SSTR-NETs, which could be superior to the gold standard β-emitting [177Lu]Lu-DOTATATE radiopharmaceutical [316]. The clinical investigation of Pb radiopharmaceuticals has been detailed in Table 26.

7.3.3. Production and Availability

212Pb is commonly produced from the decay chain of a 228Th (t1/2 = 1.9 y) generator, followed by its elution in 2M HCl using a cation exchange column with a maximum yield of 85% [319]. At high radioactivity (>37 MBq), however, the radiolytic damage of the cation exchange resin in the 228Th generator increases the back pressure and decreases the yield [319]. To circumvent this, an alternative generator using 224Ra (t1/2 = 3.7 d) was designed, which serves as a source of either 212Bi or its parent nuclide 212Pb [319]. The 224Ra/212Pb generator could elute 212Pb with a radioactivity up to ~600 MBq (16 mCi) [319]. Currently, 212Pb is mainly supplied by OranoMed and Oak Ridge National Laboratory [319]. McNeil et al. established a production protocol of 203Pb via proton irradiation of either natural thallium (Tl) or enriched 203Tl in a TR13 (13 MeV) cyclotron to create a 228Th/212Pb generator for 212Pb [312].

7.4. Radioisotopes of Radium

7.4.1. General Information

Ra has several radioisotopes, of which 223Ra and 224Ra are of considerable interest to the medical field as bone-seeking α-emitters for TAT [320]. 223Ra (t1/2 = 11.4 d) is an α-emitter that decays to 207Pb via six intermediate progenies (219Rn, 215Po,211Pb, 211Bi, 211Po, 207Tl) and delivers four α particles and two beta particles (Table 27) [320]. However, 223Ra faces challenges in quantitative imaging because of the limited abundance of short-range gamma photons (<2%) [321]. Several research studies are ongoing to investigate its dosimetry approach [322,323,324].
224Ra is a pure α-emitter that decays via a series of six daughter nuclides (220Rn, 216Po,212Pb, 212Bi, 212Po, 208Tl) and emit overall four alpha particles and two beta particles before stabilizing to 208Pb [325]. 224Ra emits abundant gamma emissions at 241 keV that can be employed for SPECT imaging [325]. 224Ra (3.6d) has a shorter half-life than 223Ra (11.4d), but its decay profile and biokinetics are like 223Ra [307].
Table 27. Decay characteristics of radioisotopes of Radium #.
Table 27. Decay characteristics of radioisotopes of Radium #.
IsotopeHalf-Life (t1/2)Decay CharacteristicsParent and Daughter NuclidesEnergy (MeV)Eγ; keV (Intensity%)
Eα maxEβ-max
223Ra11.4 dα = 100%223Ra
207Pb (stable)
144.27 (3.36)
154.2 (5.84)
323.8 (4.06)
328.2 (2.85)
224Ra3.6dα = 100%224Ra
208Pb (stable)
# Data on 223Ra are from [326,327], and data on 224Ra are from [328]. Please refer to Scheme 2.

7.4.2. Clinical Practice

From mid-1940 to 1990, [224Ra]RaCl2 of high doses (up to 140 MBq) was used to treat different bone and joint diseases, mainly in Germany, but this practice was abandoned for technical and commercial reasons [329]. During 2000–2005, the use of [224Ra]RaCl2 (low dose up to 10 MBq) was revived to treat ankylosing spondylitis patients, but this was discontinued in 2005 due to the enhanced risk of malignant disease following injection [330,331]. One of the potential drawbacks of 224Ra is the release of progeny β-emitting 212Pb with a significant half-life of 10.6 h, which could cause unwanted non-target exposure [330]. Therefore, alternative delivery strategies are of considerable interest, which could promote the retention of the daughter nuclides or mitigate their recoiling spread.
During 2007–2015, several preclinical studies investigated brachytherapy using 224Ra-loaded diffusing α-emitter radiation therapy (DaRT) wires or seeds, which minimizes the damage to surrounding normal tissues [332]. The first-in-human clinical study based on DaRT was reported in 2020 and involved the implantation of 224Ra seeds to treat squamous cancers of the skin and head [333]. Complete response to the 224Ra-DaRT treatment was observed in 22 of the 28 patients; the remaining 6 patients showed only a partial response (>30% tumor reduction) [333]. Like 224Ra, 223Ra was also studied for the treatment of bone skeletal metastasis. The first clinical study (phase I) in prostate and breast cancer patients was reported by Nilsson et al. in 2005 [334]. Later, the favorable clinical results (phase II/III) of [223Ra]RaCl2 to treat metastatic PCa led to FDA approval of [223Ra]RaCl2 (Xofigo®; Bayer) in 2013 [335,336]. Several clinical trials of 223Ra-based radionuclide therapy in combination with chemotherapy (docetaxel, paclitaxel), hormonal therapy (abiraterone, enzalutamide), and immunotherapy are ongoing (Table 28).

7.4.3. Production and Availability

223Ra is mainly produced from 227Ac/227Th generators, where 223Ra is separated from 227Ac/227Th mother radionuclides using separation columns [300,350]. On the other hand, 224Ra is usually produced from a 228Th generator, where 228Th is immobilized on actinide resin, which allows regular elution of 224Ra in 1M HCl [351].

7.5. Thorium-227

7.5.1. General Information

227Th (a progenitor of 223Ra) is an α-emitting radionuclide that decays to 223Ra, which further decays by a series of α and β emissions before stabilizing to 207Pb [352] (Table 29). 227Th can be readily chelated with 3, 2-hydroxypyridone-N-oxide (HOPO). When 227Th is conjugated with tumor-targeting moieties, they are collectively called targeted thorium-227 conjugates (TTCs) [353].

7.5.2. Clinical Practice

There are four clinical trials listed for 227Th-based TTCs registered in the US National Library of Medicine. These trials are based on 227Th-labeled anti-PSMA-HOPO (Bay 2315497) and 227Th-labeled anti-mesothelin-HOPO for the treatment of PCa (NCT03724747) [355] and mesothelioma (Bay 2287411), respectively. The remaining two trials are based on 227Th-labeled epratuzumab-HOPO (Bay 1862864) and 227Th-labeled trastuzumab-HOPO (Bay 2701439) to treat CD22-positive non-Hodgkin’s lymphoma and HER2-positive breast or gastric cancers, respectively (Table 30). 89Zr-labeled HOPO has the potential to serve as a PET surrogate for TTCs, which could support the clinical development of novel TTCs by providing crucial pharmacokinetic and pharmacodynamic information [356].

7.5.3. Production and Availability

227Th is produced as a decay product of the parent β emitter 227Ac (t1/2 = 21.8 year) [357]. The longer half-life of 227Th (t1/2 = 18.7 days) allows for the shipment of cGMP-grade 227Th solution worldwide [357].
Table 30. Clinical applications of 227Th-labeled radiopharmaceuticals.
Table 30. Clinical applications of 227Th-labeled radiopharmaceuticals.
RadiopharmaceuticalsTargetsNCT Number ^Disease
[227Th]Th-anti PSMA (BAY2315497)PSMANCT03724747 (Phase I; ongoing)Metastatic castration-resistant prostate cancer [355]
[227Th]Th-anti Mesothelin (BAY2287411)MesothelinNCT03507452 (Phase I; completed)Advanced recurrent serous ovarian, malignant peritoneal mesothelioma, pancreatic adenocarcinoma [358]
[227Th]Th-trastuzumab (BAY2701439)HER2+NCT04147819 (Phase I; ongoing)Cancer with HER2 + expression [359]
[227Th]Th-epratuzumab (BAY1862864)CD22NCT02581878 (Phase I; completed)Non-Hodgkin lymphoma [360]
NCT: National clinical trial, PSMA: Prostate-specific membrane antigen, HER2+: Human epidermal growth factor 2, CD22: Cluster of differentiation 22, ^ and data accessed on 15 August 2023.

7.6. Radioisotopes of Astatine

7.6.1. General Information

Astatine-221 (211At) is an α-emitting therapeutic radionuclide that decays into two branches either by α-emission (42%) to 207Bi (t1/2 = 33.9 y) or by EC (58%) to 211Po (t1/2 = 516 ms); both eventually decay to a stable 207Pb [361]. Each decay yields one α particle and the emission of characteristic X-rays (70–90 keV) through the decay of 211Po and could be used for SPECT imaging and quantification of 211At [361]. 209At (t1/2 = 5.4 h) is another isotope that predominantly decays by β+ emission (96%) and has been introduced as a theranostic pair to 211At (Table 31) [361]. 211At is a more attractive radionuclide than other α-emitting radionuclides because of its suitable half-life of 7.2 h, the absence of long-lived and/or toxic progenies, and its feasibility to be produced in decent quantities [361].

7.6.2. Clinical Practice

Although 211At-labeled TAT agents were discovered more than 30 years ago, only a few clinical studies using 211At-labeled Abs have been published. Zalutsky et al. reported on the application of 211At-labeled chimeric anti-tenascin mAb 81C6 (71–347 MBq) in recurrent brain tumor patients with an encouraging median survival time of 52 weeks compared to 23 weeks reported for recurrent glioblastoma multiforme patients treated with best care [362]. Another clinical study of intraperitoneal α particle therapy was reported using [211At]At-MX35(Fab) in relapsed ovarian cancer patients [363]. The results showed that there was no apparent radiation-induced toxicity discovered in patients for up to 12 years and no decreased tolerance to relapse therapy. The clinical investigation of 211At-labeled radiopharmaceuticals is summarized in Table 32.

7.6.3. Production and Availability

The most common route is the cyclotron/accelerator-based production of 211At through alpha irradiation of 209Bi (natural Bi) via a 209Bi(α,2n)211At nuclear reaction [364,365]. However, only a limited number of cyclotrons with α-beam and with > 25 MeV energy are available in the field, limiting the overall 211At availability [364]. Other methods include the use of 211Rn/211At generators [366]. One of the potential advantages of using 211Rn/211At generators is the longer half-life of 211Rn (t1/2 = 14.6 h) compared with 211At (t1/2 = 7.2 h), facilitating wider distribution of 211At.
Table 32. Clinical applications of Astatine-211-labeled radiopharmaceuticals.
Table 32. Clinical applications of Astatine-211-labeled radiopharmaceuticals.
RadiopharmaceuticalsTargetsNCT Number ^Disease
Sodium Astatide ([211At]NaAt)-NCT05275946 (Phase I; ongoing)Thyroid cancer [367]
[211At]At- 81C6Glial fibrillary acidic proteinNCT00003461 (Phase I/II; completed)Metastatic cancer, brain and central nervous system tumors, neuroblastoma [368]
[211At]At- bc8-b10CD45NCT04083183 (Phase I/II; ongoing)
NCT03670966 (Phase I/II; ongoing)
Non-malignant neoplasm [369]
Acute lymphoblastic leukemia in remission [370]
[211At]At-OKT-B10CD3NCT04466475 (Phase I; ongoing)Plasma cell myeloma [371]
NCT: National clinical trial, CD45: Cluster of differentiation, CD3: Cluster of differentiation 3, ^ and data accessed on 15 August 2023.

8. Conclusions

In summary, the development of radiometal-based radiopharmaceuticals, including their production, purification, bifunctional chelating agents, and biomarker discoveries, have significantly advanced the application of various radiometals in medicine in the last two decades. Both radiometal-based imaging and radionuclide therapy are changing the lives of patients on a daily basis due to the advancements made in the last 20 years. The field of α-emitting radiotherapy is emerging. Several clinical trials are currently under investigation. Further advances in the production and availability of these α-emitters along with the management of radioactive progeny should permit the cost-effective clinical adoption of TAT compared to traditional chemotherapeutics. Indeed, the future of the radiometal-based radiopharmaceutical industry appears to be very bright.

Author Contributions

S.S. and M.K.P. both contributed to manuscript writing, reviewing, and editing. All authors have read and agreed to the published version of the manuscript.


The writing of the review article was financially supported by the Division of Nuclear Medicine, Department of Radiology, Mayo Clinic, Rochester, MN, USA.

Institutional Review Board Statement

Not applicable.

Informed Consent Statement

Not applicable.

Data Availability Statement

Data are contained within the article.


The authors thank Desiree Lanzino for her assistance in editing the manuscript. The authors would like to thank the Division of Nuclear Medicine, Department of Radiology, Mayo Clinic, Rochester, MN, USA for financially supporting the writing of this manuscript.

Conflicts of Interest

The authors declare no conflict of interest.


AML=Acute myeloid leukemia
CD8=Cluster of differentiation 8
CD38=Cluster of differentiation 38
CD20=Cluster of differentiation 20
CEA=Carcinoembryonic antigen
CERN=European Council for Nuclear Research
DaRT=Diffusing alpha-emitters radiation therapy
EC=Electron capture
EGFR=Epidermal growth factor receptor
FAPI=Fibroblast activation protein inhibitor
FDA=Food and Drug Administration
GBM=Glioblastoma Multiforme
GMP=Good manufacturing practice
HER2=Human epidermal growth factor 2
IART®=Intra-operative avidination for radionuclide therapy
ISOLDE=Isotope separation on-line
LET=Linear energy transfer
mAb=Monoclonal antibody
MAE=Meitner–Auger electrons
mCRPC=Metastatic castrate-resistant prostate cancer
NCT=National clinical trial
NET=Neuroendocrine tumor
PCa=Prostate cancer
PDL-1=Programmed cell death ligand-1
PET=Positron emission tomography
PRRT=Peptide receptor radionuclide therapy
PSA=Prostate-specific antigen
PSMA=Prostate-specific membrane antigen
SPECT=Single photon emission computed tomography
SSTR2=Somatostatin-targeting receptor 2
SUV=Standardized uptake value
TAT=Targeted alpha therapy
TRT=Targeted radionuclide therapy
TTC=Targeted thorium conjugates
VEGF=Vascular endothelial growth factor


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Figure 1. Comparison of beta and alpha radionuclide therapies.
Figure 1. Comparison of beta and alpha radionuclide therapies.
Pharmaceuticals 16 01460 g001
Scheme 1. Decay scheme for various radionuclides.
Scheme 1. Decay scheme for various radionuclides.
Pharmaceuticals 16 01460 sch001
Scheme 2. Decay scheme for various α-emitting radionuclides.
Scheme 2. Decay scheme for various α-emitting radionuclides.
Pharmaceuticals 16 01460 sch002
Table 1. Decay characteristics of copper radioisotopes used in radiopharmaceuticals #.
Table 1. Decay characteristics of copper radioisotopes used in radiopharmaceuticals #.
IsotopeHalf-Life (t1/2)Decay CharacteristicsEnergiesEγ; keV
(Intensity %)
60Cu23.7 minβ+ = 93%
EC = 7%
970-1332.5 (88)
1791.6 (45.4)
826.4 (21.7)
61Cu3.33 hβ+ = 61%
EC = 39%
500-282.95 (12.7)
656 (10.4)
62Cu9.76 minβ+ = 97%
EC = 2%
2910-511 (194)
64Cu12.70 hβ = 38.5%
β+ = 17.6%
EC = 43.9%
2781911345.77 (0.475)
67Cu61.83 hβ = 100%-141184.57 (48.7)
# Data on 60/61/64/67Cu are from [24] and data on 62Cu are from [25]. Please refer to Scheme 1A.
Table 2. Clinical applications of various 64/67Cu-labeled radiopharmaceuticals.
Table 2. Clinical applications of various 64/67Cu-labeled radiopharmaceuticals.
RadiopharmaceuticalsTargetsNCT Number ^Disease [Ref.]
[64Cu]Cu-ATSMHypoxia-targetedNCT03951337 (Phase II; ongoing)Rectum cancer [32]
[64Cu]Cu-DOTA-trastuzumabHER2+NCT02827877 (Phase II; ongoing)Breast cancer [56]
[64Cu]Cu-DOTA-M5ACEANCT05245786 (Early phase I; ongoing)Rectal cancer [57]
[64Cu]Cu- SarTATESSTRNCT04438304 (Phase II; ongoing)Neuroendocrine tumors [58]
[64Cu]Cu-TP3805VPAC1NCT02603965; (Phase I; completed)Prostate cancer [59]
[64Cu]Cu-DOTA-AE105uPARNCT02139371 (Early phase I; completed)Breast, prostate, and bladder cancer [60]
[64Cu]Cu-SAR-bisPSMAPSMANCT04839367 (Phase I; completed)
NCT05249127 (Phase I/II; ongoing)
Prostate neoplasms [61]
Recurrent prostate neoplasm [62]
[67Cu]Cu- SarTATESSTRNCT03936426 (Phase I/IIa; completed),
NCT04023331 (Phase I/IIa; ongoing)
Meningioma [63]
Neuroblastoma [64]
[64/67Cu]Cu-SAR-bisPSMAPSMANCT04868604 (Phase I/IIa; ongoing)Castration-resistant prostate cancer [65]
NCT: National clinical trial, uPAR: Urokinase plasminogen activator receptor, CEA: Carcinoembryonic antigen, VPAC1: Vasoactive intestinal polypeptide, SSTR: Somatostatin receptors, PSMA: Prostate-specific membrane antigen, ^ and data accessed on 15 August 2023.
Table 3. Decay characteristics of the three main radioisotopes of gallium #.
Table 3. Decay characteristics of the three main radioisotopes of gallium #.
IsotopeHalf-Life (t1/2)Decay CharacteristicsEnergyEγ; keV (Intensity %)
Eβ+avg (keV)
66Ga9.49 hβ+ = 57%17501039.22 (37)
EC = 43%
67Ga3.26 dEC = 100%-93.31 (38.81)
68Ga67.71 minβ+ = 88.91%829.51077.34 (3.22)
EC = 11.09%
# Data on 66/67/68Ga are from [78]. Please refer to Scheme 1A.
Table 7. Decay characteristics of commonly used radioisotopes of scandium #.
Table 7. Decay characteristics of commonly used radioisotopes of scandium #.
IsotopeHalf-Life (t1/2)Decay CharacteristicsEnergiesEγ; keV (Intensity%)
Eβ+avg (keV)Eβavg (keV)
43Sc3.9 hβ+ = 88%476-372(23)
EC = 12%
44Sc4.0 hβ+ = 94%632-1157(100)
EC = 6%
47Sc3.35 dβ = 100%-162159(68)
#Data on 43/44/47Sc are from [150]. Please refer to decay Scheme 1A.
Table 8. Decay characteristics of leading radioisotopes of terbium #.
Table 8. Decay characteristics of leading radioisotopes of terbium #.
IsotopeHalf-Life (t1/2)Decay CharacteristicsEnergyEγ; keV (Intensity %)
Eβ+avg (keV)Eα avg
4.12 hα = 16.7%7303967-165 (26), 352 (29)
β+ = 7.1%388.6 (18)
EC = 76.2%652.1 (16)
17.5 hβ+ = 17%1080--344.3 (65)
EC = 83%586.3(9.4)
5.32 dEC = 100%---86.55 (32)
105.3 (25)
/MAE therapy)
6.89 dβ = 100%--15425.65 (23)
48.92 (17)
74.57 (10)
# Data on 149/152/155/161Tb are from [167]. Please refer to decay Scheme 1A.
Table 9. Clinical applications of terbium-labeled radiopharmaceuticals under investigation.
Table 9. Clinical applications of terbium-labeled radiopharmaceuticals under investigation.
RadiopharmaceuticalsTargetsNCT Number ^Disease
[161Tb]Tb-DOTA-LM3SSTR2NCT05359146 (Early phase 1; recruiting)Neuroendocrine neoplasia or gastroenteropancreatic neuroendocrine tumor [179]
[161Tb]Tb-PSMA-I&TPSMANCT05521412 (Phase I/II; recruiting)Prostate cancer or metastatic castration-resistant prostate cancer [180]
NCT: National clinical trial, SSTR2: Somatostatin-targeting receptor 2, PSMA: Prostate-specific membrane antigen, ^ and data accessed on 15 August 2023.
Table 10. Decay characteristics of PET isotopes of zinc #.
Table 10. Decay characteristics of PET isotopes of zinc #.
IsotopeHalf-Life (t1/2)Decay CharacteristicsEβ+avg (keV)Eγ; keV (Intensity%)
62Zn9.26 hβ+ = 8.2%259508 (15), 550 (15)
600 (26)
63Zn38.47 minβ+ = 93%992670 (8)
960 (7)
65Zn243.9 dβ+ = 98%142.51110 (50.6)
# Data on 62/63/65Zn are from [184]. Please refer to Scheme 1A.
Table 11. Decay characteristics of Technetium-99 m #.
Table 11. Decay characteristics of Technetium-99 m #.
IsotopeHalf-Life (t1/2)Decay CharacteristicsEγ; keV (Intensity %)
99mTc6.0 hIT = 100%140.51 (98.6)
# Data on 99mTc are from [188]. Please refer to Scheme 1B.
Table 12. Clinical applications of 99mTc-labeled radiopharmaceuticals.
Table 12. Clinical applications of 99mTc-labeled radiopharmaceuticals.
RadiopharmaceuticalsTargetsNCT Number ^Disease
[99mTc]Tc-tilmanoceptLymph nodeNCT02201420 (Phase II; completed)Kaposi’s sarcoma [196]
[99m Tc]Tc-EC20FolateNCT01689714 (Phase II; completed)Ovarian or recurrent endometrial carcinoma [197]
[99m Tc]Tc-Tetrofosmin-NCT02971319 (Phase II; completed)Glioma [198]
[99m Tc]Tc-Sestamibi-NCT05042687 (Phase not applicable)Breast cancer [199]
[99m Tc]Tc-HYNIC TOC EDAASSTRNCT02691078 (Phase II completed)Neuroendocrine tumors [200]
[99m Tc]Tc-MP-1404PSMANCT02615067 (Phase III completed)Prostate cancer [201]
[99m Tc]Tc-MP-1404
[99m Tc]Tc-MP-1405
PSMANCT01261754 (Phase I; completed)Prostate cancer [202]
[99m Tc]Tc-PSMA I&SPSMANCT04832958 (Phase II; ongoing)Prostate cancer [203]
[99m Tc]Tc-labeled albumin in macroaggregates (MAA) and in microspheres (B20)-NCT01186263
(Phase II; completed)
Colorectal cancer, liver metastasis [204]
NCT: National clinical trial, PSMA: Prostate-specific molecular antigen, SSTR: Somatostatin-targeting receptor, ^ and data accessed on 15 August 2023.
Table 13. Decay characteristics of radioisotopes of indium #.
Table 13. Decay characteristics of radioisotopes of indium #.
IsotopeHalf-Life (t1/2)Decay CharacteristicsEβ+avg (keV)Eγ; keV (Intensity %)
110mIn69.1minβ+ = 61.3%1011657.75(97.74)
EC = 38%
111In2.8 dEC = 100%-245.35(94.1)
# Data on 110m/111In are from [78]. Please refer to Scheme 1B.
Table 15. Decay characteristics of Yttrium-90 #.
Table 15. Decay characteristics of Yttrium-90 #.
IsotopeHalf-Life (t1/2)Decay CharacteristicsEnergy
Eβmax (MeV)Eβavg (MeV)
90Y64.0 hβ = 100%2.2840.933
# Data on 90Y are from [223]. Please refer to Scheme 1C.
Table 17. Decay characteristics of 186/188Re #.
Table 17. Decay characteristics of 186/188Re #.
IsotopeHalf-Life (t1/2)Decay CharacteristicsEβavg
Eγ; keV (Intensity%)
186Re90 hβ = 92.59%346.7137.15 (9.47)
EC = 7.41%106 (12.1)
188Re17.0 hβ = 100%763155.04 (15.49)
478 (1.076%)
# Data on 186/188Re are from [251]. Please refer to Scheme 1C.
Table 19. Decay characteristics of Lutetium-177 #.
Table 19. Decay characteristics of Lutetium-177 #.
IsotopeHalf-Life (t1/2)Eβ-max (keV)Eϒ; keV (Intensity%)
177Lu6.647 d497 (78.6%)
384 (9.1%)
176 (12.2%)
208 (11%)
113 (6.6%)
# Data on 177Lu are from [271]. Please refer to decay Scheme 1C.
Table 20. Clinical applications of 177Lu-labeled radiopharmaceuticals.
Table 20. Clinical applications of 177Lu-labeled radiopharmaceuticals.
RadiopharmaceuticalsTargetsNCT Number ^Disease [Ref.]
[177Lu]Lu-PSMA-617 (PLUVICTO ®)PSMANCT03511664 (Phase III; ongoing) Metastatic prostate cancer [279]
223Ra + [177Lu]Lu-PSMA- I & TPSMANCT05383079 (phase II; recruiting)Metastatic castration-resistant prostate cancer [280]
Cabozantinib in Combination With [177Lu]Lu- DOTATATE (LuTATE)SSTR2NCT05249114 (Phase Ib; ongoing)Neuroendocrine tumors [281]
capecitabine (CAP)/temozolomide (TEM) + [177Lu]Lu- DOTATATE (LuTATE)SSTR NCT02358356 (phase II; completed)Mid gut or pancreatic neuroendocrine tumors [282]
[177Lu]Lu- DOTATATE (Lutathera) SSTR2NCT03206060 (phase II; ongoing)Pheochromocytoma/Paraganglioma, neuroendocrine tumor [283]
[177Lu]Lu-EdotreotideSSTR NCT04919226 (phase III; ongoing)Gastroenteropancreatic neuroendocrine tumors [284]
[177Lu]Lu- catalase -NCT05985278 (Early phase 1; ongoing)Advanced malignant neoplasm [285]
[177Lu]Lu-EB-FAPIFAPNCT05400967 (Early phase 1; ongoing)Metastatic tumors [286]
[177Lu]Lu-DOTA-girentuximabCarbonic anhydrase IXNCT02002312 (phase II; completed) Metastatic clear cell renal cancer [287]
NCT: National clinical trial, SSTR: Somatostatin receptors, FAP: Fibroblast activation protein, ^ and data accessed on 15 August 2023.
Table 23. Decay characteristics of Actinimum-225 #.
Table 23. Decay characteristics of Actinimum-225 #.
IsotopeHalf-Life (t1/2)Decay Characteristics225Ac and Daughter NuclidesEnergies (MeV)Eγ; keV (Intensity%)
EαmaxEβ max
225Ac9.9 dα = 100%225Ac
209Bi (stable)

213Bi-100 (1)
221Fr-218 (11.4)
213Bi-440 (26)
209Tl-1567 (99.7)
# Data on 225Ac are from [300]. Please refer to Scheme 2.
Table 24. Clinical application of Actinium-225-labeled radiopharmaceuticals.
Table 24. Clinical application of Actinium-225-labeled radiopharmaceuticals.
RadiopharmaceuticalsTargetsNCT Number ^Disease
[225Ac]Ac-lintuzumab with VenetoclaxBCL-2NCT03867682 (Phase I/II; ongoing)Acute and relapsed myeloid leukemia [304]
[225Ac]Ac-DOTA-DaratumumabCD38NCT05363111 (Phase I; ongoing)Recurrent plasma cell myeloma [305]
[225Ac]Ac-FPI-1434IGF-1RNCT03746431 (Phase I/II; ongoing)Advanced solid tumor, endometrial cancer, ovarian, cervical cancer [306]
[225Ac]Ac-DOTA-M5ACEANCT05204147 (Phase I; ongoing)Advanced and metastatic cancer [307]
(Phase I; ongoing)
Castration-resistant prostate cancer [308]
[225Ac]Ac-J591PSMANCT03276572 (Phase I; ongoing)Prostate cancer [309]
NCT: National clinical trial, BCL-2: B-cell lymphoma 2, CD38: Cluster of differentiation 38, IGF-1R: Type 1 insulin-like growth factor receptor, CEA: Carcinoembryonic antigen, PSMA: Prostate-specific membrane antigen, ^ and data accessed on 15 August 2023.
Table 25. Decay characteristics of lead #.
Table 25. Decay characteristics of lead #.
IsotopeHalf-Life (t1/2)Decay CharacteristicsParent and Daughter NuclidesEnergiesEγ; keV; (Intensity%)
Eβ- max
203Pb51.9hEC = 100%203Tl (stable)--279 (81)
212Pb10.6hβ = 100%212Pb
208Pb (stable)
212Pb-238.6 (43.6)
212Bi-727.3 (6.6)
208Tl-277.4 (6.3), 510.8 (22.6), 583.2 (84.5), 763 (1.8), 860.6 (12.4), 2614.5 (99.2)
# Data on 203Pb are from [312] and data on 212Pb are from [296]. Please refer to Scheme 2.
Table 26. Clinical applications of 212lead-212-labeled radiopharmaceuticals.
Table 26. Clinical applications of 212lead-212-labeled radiopharmaceuticals.
RadiopharmaceuticalsTargetsNCT Number ^Disease
[212Pb]Pb-DOTAMTATE (Alpha MedixTM)SSTRNCT05153772
(Phase II; ongoing)
Neuroendocrine tumors [317]
(Phase I; completed)
Breast, ovarian, peritoneal, pancreatic, and stomach neoplasm [318]
NCT: National clinical trial, SSTR: Somatostatin receptors, HER2+: Human epidermal growth factor 2, ^ and data accessed on 15 August 2023.
Table 28. Clinical applications of 223Ra in combination with other therapies.
Table 28. Clinical applications of 223Ra in combination with other therapies.
RadiopharmaceuticalsTargetsNCT Number ^Disease
[223Ra]Ra-dichlorideSkeletal metastasisNCT01833520 (Phase II; completed)Sarcoma [337]
[223Ra]Ra-dichloride + NiraparibPARP inhibitorNCT03076203 (Phase I; completed)Prostate cancer metastatic to bone, stage IV prostate cancer, hormone refractory prostate cancer [338]
[223Ra]Ra-dichloride + Abiraterone, Prednisone/PrednisoloneCYP17 inhibitorNCT02043678 (Phase III; active)Prostate cancer [339]
[223Ra]Ra-dichloride + EnzalutamideAR inhibitorNCT02199197 (Phase II; completed) NCT03305224 (Phase II; ongoing)Prostate cancer, [340], bone metastatic prostate cancer [341]
[223Ra]Ra-dichloride + DenosumabCytokine RANKLNCT02366130 (Phase II; completed)Breast carcinoma [342]
[223Ra]Ra-dichloride + PaclitaxelTubulinNCT02442063 (Phase I; completed)Neoplasm, bone disease [343]
[223Ra]Ra-dichloride + DocetaxelP300NCT03574571 (Phase III; ongoing)Prostate cancer [344]
[223Ra]Ra-dichloride + Leuprolide acetate,GnRH-receptor agonistNCT03361735 (Phase II; ongoing)Prostate cancer [345]
[223Ra]Ra-dichloride + PembrolizumabPDL-1NCT03093428 (Phase II; ongoing)Prostate cancer [346]
[223Ra]Ra-dichloride + AtezolizumabPDL-1NCT02814669 (Phase I; completed)Castration-resistant prostate cancer [347]
Alpha-DaRT seeds (224Ra containing 316LVM tubes)Implantation sitesNCT04002479 (Phase not applicable) NCT03970967 (Phase not applicable)Metastatic pancreatic cancer [348]
Metastatic breast cancer [349]
NCT: National clinical trial, PARP: Polyadenosine diphosphate-ribose polymerase, CYP17: Cytochrome P450 17 α-hydroxylase/17,20-lyase, AR inhibitor: Androgen receptors, RANKL: Receptor activator of nuclear factor-kB ligand, GnRH-receptor agonist: Gonadotropin-releasing hormone, PDL-1: Programmed cell death ligand-1, ^ and data accessed on 15 August 2023.
Table 29. Decay characteristics of thorium-227, which follow a decay chain of radium-223 #.
Table 29. Decay characteristics of thorium-227, which follow a decay chain of radium-223 #.
IsotopeHalf-Life (t1/2)227Th and Daughter NuclidesEαmax (MeV)
227Th18.7 dα = 100%227Th
207Pb (stable)
# Data on 227Th are from [354]. Please refer to Scheme 2.
Table 31. Decay characteristics of Astatine-221 #.
Table 31. Decay characteristics of Astatine-221 #.
IsotopeHalf-Life (t1/2)Decay Characteristics211At and Daughter NuclidesEαmax
Eγ; keV
211At7.2 hα = 42%
EC = 58%
207Pb (stable)
211Po-569.7, 897.8
# Data on 211At are from [361]. Please refer to Scheme 2.
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