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Pharmaceutics
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Recent Advances in Radiopharmaceutics, 2nd Edition
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Recent Advances in Radiopharmaceutics, 2nd Edition

A special issue of Pharmaceutics (ISSN 1999-4923). This special issue belongs to the section "Drug Targeting and Design".

Deadline for manuscript submissions: 10 August 2024 | Viewed by 8004

Special Issue Editor

Dr. Masato Kobayashi

E-Mail Website
Guest Editor
School of Health Sciences, Institute of Medical, Pharmaceutical and Health Sciences, Kanazawa University, Kanazawa, Japan
Interests: PET; SPECT; multimodality; imaging analysis; pharmacokinetics
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

The development of radiopharmaceuticals is important for diagnosis and/or radionuclide therapy in nuclear medicine with positron emission tomography (PET) and single-photon emission computed tomography (SPECT). It also has translational potential from preclinical study to clinical in oncology, neurodegenerative diseases, cardiovascular diseases, etc., for personalized medicine. Integrative imaging and therapy, in combination with other modalities, such as magnetic resonance imaging, ultrasonography, near-infrared imaging, etc., may move personalized medicine further. In addition, advances in PET and SPECT scanners emphasize the usefulness of radiopharmaceuticals.

This Special Issue focuses on the synthesis and evaluation of new radiopharmaceuticals, other applications of radiopharmaceuticals for clinical use, and the combination of radionuclides with other modalities. Novel PET and SPECT machines are also a target. However, the areas of interest are not limited to these keywords.

Dr. Masato Kobayashi
Guest Editor

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Pharmaceutics is an international peer-reviewed open access monthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2900 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • PET
  • SPECT
  • radiopharmaceutical
  • multimodality
  • imaging
  • biofunction
  • pharmacokinetics
  • imaging scanner

Published Papers (6 papers)

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Research

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19 pages, 5235 KiB  
Article
68Ga-DOTA-D-Alanine-BoroPro Radiotracer for Imaging of the Fibroblast Activation Protein in Malignant and Non-Malignant Diseases
by Diana Trujillo-Benítez, Myrna Luna-Gutiérrez, José G. Aguirre-De Paz, Pedro Cruz-Nova, Gerardo Bravo-Villegas, Joel E. Vargas-Ahumada, Paola Vallejo-Armenta, Enrique Morales-Avila, Nallely Jiménez-Mancilla, Rigoberto Oros-Pantoja, Clara Santos-Cuevas, Erika Azorín-Vega, Blanca Ocampo-García and Guillermina Ferro-Flores
Pharmaceutics 2024, 16(4), 532; https://doi.org/10.3390/pharmaceutics16040532 - 12 Apr 2024
Viewed by 260
Abstract
Recently, we reported a new fibroblast activation protein (FAP) inhibitor radiopharmaceutical based on the 99mTc-((R)-1-((6-hydrazinylnicotinoyl)-D-alanyl) pyrrolidin-2-yl) boronic acid (99mTc-HYNIC-D-Alanine-BoroPro)(99mTc-HYNIC-iFAP) structure for tumor microenvironment SPECT imaging. This research aimed to synthesize 68Ga-[2,2′,2″,2‴-(2-(4-(2-(5-(((S)-1-((S)-2-boronopyrrolidin-1-yl)-1-oxopropan-2-yl)carbamoyl)pyridin-2-yl)hydrazine-1-carbothioamido)benzyl)-1,4,7,10-tetraazacyclododecane-1,4,7,10-tetrayl)tetraacetic acid] (68Ga-DOTA-D-Alanine-BoroPro)(68Ga-iFAP) [...] Read more.
Recently, we reported a new fibroblast activation protein (FAP) inhibitor radiopharmaceutical based on the 99mTc-((R)-1-((6-hydrazinylnicotinoyl)-D-alanyl) pyrrolidin-2-yl) boronic acid (99mTc-HYNIC-D-Alanine-BoroPro)(99mTc-HYNIC-iFAP) structure for tumor microenvironment SPECT imaging. This research aimed to synthesize 68Ga-[2,2′,2″,2‴-(2-(4-(2-(5-(((S)-1-((S)-2-boronopyrrolidin-1-yl)-1-oxopropan-2-yl)carbamoyl)pyridin-2-yl)hydrazine-1-carbothioamido)benzyl)-1,4,7,10-tetraazacyclododecane-1,4,7,10-tetrayl)tetraacetic acid] (68Ga-DOTA-D-Alanine-BoroPro)(68Ga-iFAP) as a novel radiotracer for PET imaging and evaluate its usefulness for FAP expression in malignant and non-malignant tissues. The coupling of p-SCN-benzene DOTA with HYNIC-iFAP was used for the chemical synthesis and further labeling with 68Ga. Radiochemical purity was verified by radio-HPLC. The specificity of 68Ga-iFAP was evaluated in HCT116 cells, in which FAP expression was verified by immunofluorescence and Western blot. Biodistribution and biokinetic studies were performed in murine models. 68Ga-iFAP uptake at the myocardial level was assessed in mice with induced infarction. First-in-human images of 68Ga-iFAP in healthy subjects and patients with myocardial infarction, glioblastoma, prostate cancer, and breast cancer were also obtained. DOTA-D-Alanine BoroPro was prepared with a chemical purity of 98% and was characterized by UPLC mass spectroscopy, FT-IR, and UV-vis. The 68Ga-iFAP was obtained with a radiochemical purity of >95%. In vitro and in vivo studies demonstrated 68Ga-iFAP-specific recognition for FAP, rapid renal elimination, and adequate visualization of the glioblastoma, breast tumor, prostate cancer, and myocardial infarction sites. The results of this research justify further dosimetry and clinical trials to establish the specificity and sensitivity of 68Ga-iFAP PET for FAP expression imaging. Full article
(This article belongs to the Special Issue Recent Advances in Radiopharmaceutics, 2nd Edition)
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18 pages, 2948 KiB  
Article
Preparation of 18F-Labeled Tracers Targeting Fibroblast Activation Protein via Sulfur [18F]Fluoride Exchange Reaction
by Austin Craig, Jürgen Kogler, Markus Laube, Martin Ullrich, Cornelius K. Donat, Robert Wodtke, Klaus Kopka and Sven Stadlbauer
Pharmaceutics 2023, 15(12), 2749; https://doi.org/10.3390/pharmaceutics15122749 - 10 Dec 2023
Viewed by 1148
Abstract
Early detection and treatment of cancers can significantly increase patient prognosis and enhance the quality of life of affected patients. The emerging significance of the tumor microenvironment (TME) as a new frontier for cancer diagnosis and therapy may be exploited by radiolabeled tracers [...] Read more.
Early detection and treatment of cancers can significantly increase patient prognosis and enhance the quality of life of affected patients. The emerging significance of the tumor microenvironment (TME) as a new frontier for cancer diagnosis and therapy may be exploited by radiolabeled tracers for diagnostic imaging techniques such as positron emission tomography (PET). Cancer-associated fibroblasts (CAFs) within the TME are identified by biomarkers such as fibroblast activation protein alpha (FAPα), which are expressed on their surfaces. Targeting FAPα using small-molecule 18F-labeled inhibitors (FAPIs) has recently garnered significant attention for non-invasive tumor visualization using PET. Herein, two potent aryl-fluorosulfate-based FAPIs, 12 and 13, were synthetically prepared, and their inhibition potency was determined using a fluorimetric FAP assay to be IC50 9.63 and 4.17 nM, respectively. Radiofluorination was performed via the sulfur [18F]fluoride exchange ([18F]SuFEx) reaction to furnish [18F]12 and [18F]13 in high activity yields (AY) of 39–56% and molar activities (Am) between 20–55 GBq/µmol. In vitro experiments focused on the stability of the radiolabeled FAPIs after incubation with human serum, liver microsomes and liver cytosol. Preliminary PET studies of the radioligands were performed in healthy mice to investigate the in vivo biodistribution and 18F defluorination rate. Fast pharmacokinetics for the FAP-targeting tracers were retained and considerable bone uptake, caused by either 18F defluorination or radioligand accumulation, was observed. In summary, our findings demonstrate the efficiency of [18F]SuFEx as a radiolabeling method as well as its advantages and limitations with respect to PET tracer development. Full article
(This article belongs to the Special Issue Recent Advances in Radiopharmaceutics, 2nd Edition)
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17 pages, 5361 KiB  
Article
99mTc-Labeled Cyclic Peptide Targeting PD-L1 as a Novel Nuclear Imaging Probe
by Guillermina Ferro-Flores, Blanca Ocampo-García, Pedro Cruz-Nova, Myrna Luna-Gutiérrez, Gerardo Bravo-Villegas, Erika Azorín-Vega, Nallely Jiménez-Mancilla, Emiliano Michel-Sánchez, Osvaldo García-Pérez, Nancy Lara-Almazán and Clara Santos-Cuevas
Pharmaceutics 2023, 15(12), 2662; https://doi.org/10.3390/pharmaceutics15122662 - 23 Nov 2023
Cited by 1 | Viewed by 966
Abstract
Recent cancer therapies have focused on reducing immune suppression in the tumor microenvironment to prevent cancer progression and metastasis. PD-1 is a checkpoint protein that stops the immune response and is expressed on immune T cells. Cancer cells express a PD-1 ligand (PD-L1) [...] Read more.
Recent cancer therapies have focused on reducing immune suppression in the tumor microenvironment to prevent cancer progression and metastasis. PD-1 is a checkpoint protein that stops the immune response and is expressed on immune T cells. Cancer cells express a PD-1 ligand (PD-L1) to bind to the T-cell surface and activate immunosuppressive pathways. This study aimed to design, synthesize, and evaluate a 99mTc-labeled PD-L1-targeting cyclic peptide inhibitor (99mTc-iPD-L1) as a novel SPECT radiopharmaceutical for PD-L1 expression imaging. AutoDock software (version 1.5) was used to perform molecular docking for affinity calculations. The chemical synthesis was based on the coupling reaction of 6-hydrazinylpyridine-3-carboxylic acid with a 14-amino-acid cyclic peptide. iPD-L1 was prepared for 99mTc labeling. Radio-HPLC was used to verify radiochemical purity. The stability of the radiopeptide in human serum was evaluated by HPLC. iPD-L1 specificity was assessed by SDS-PAGE. [99mTc]Tc-iPD-L1 cellular uptake in PD-L1-positive cancer cells (HCC827 and HCT116) and biodistribution in mice with induced tumors were also performed. One patient with advanced plantar malignant melanoma received [99mTc]Tc-iPD-L1. The iPD-L1 ligand (AutoDock affinity: −6.7 kcal/mol), characterized by UPLC mass, FT-IR, and UV–Vis spectroscopy, was obtained with a chemical purity of 97%. The [99mTc]Tc-iPD-L1 was prepared with a radiochemical purity of >90%. In vitro and in vivo analyses demonstrated [99mTc]Tc-iPD-L1 stability (>90% at 24 h) in human serum, specific recognition for PD-L1, high uptake by the tumor (6.98 ± 0.89% ID/g at 1 h), and rapid hepatobiliary and kidney elimination. [99mTc]Tc-iPD-L1 successfully detected PD-L1-positive lesions in a patient with plantar malignant melanoma. The results obtained in this study warrant further dosimetric and clinical studies to determine the sensitivity and specificity of [99mTc]Tc-iPD-L1/SPECT for PD-L1 expression imaging. Full article
(This article belongs to the Special Issue Recent Advances in Radiopharmaceutics, 2nd Edition)
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18 pages, 2152 KiB  
Article
[111In]In/[177Lu]Lu-AAZTA5-LM4 SST2R-Antagonists in Cancer Theranostics: From Preclinical Testing to First Patient Results
by Berthold A. Nock, Panagiotis Kanellopoulos, Euy Sung Moon, Maritina Rouchota, George Loudos, Sanjana Ballal, Madhav P. Yadav, Chandrasekhar Bal, Prashant Mishra, Parvind Sheokand, Frank Roesch and Theodosia Maina
Pharmaceutics 2023, 15(3), 776; https://doi.org/10.3390/pharmaceutics15030776 - 26 Feb 2023
Cited by 4 | Viewed by 1835
Abstract
Aiming to expand the application of the SST2R-antagonist LM4 (DPhe-c[DCys-4Pal-DAph(Cbm)-Lys-Thr-Cys]-DTyr-NH2) beyond [68Ga]Ga-DATA5m-LM4 PET/CT (DATA5m, (6-pentanoic acid)-6-(amino)methy-1,4-diazepinetriacetate), we now introduce AAZTA5-LM4 (AAZTA5, 1,4-bis(carboxymethyl)-6-[bis(carboxymethyl)]amino-6-[pentanoic-acid]perhydro-1,4-diazepine), allowing for the convenient coordination of trivalent [...] Read more.
Aiming to expand the application of the SST2R-antagonist LM4 (DPhe-c[DCys-4Pal-DAph(Cbm)-Lys-Thr-Cys]-DTyr-NH2) beyond [68Ga]Ga-DATA5m-LM4 PET/CT (DATA5m, (6-pentanoic acid)-6-(amino)methy-1,4-diazepinetriacetate), we now introduce AAZTA5-LM4 (AAZTA5, 1,4-bis(carboxymethyl)-6-[bis(carboxymethyl)]amino-6-[pentanoic-acid]perhydro-1,4-diazepine), allowing for the convenient coordination of trivalent radiometals of clinical interest, such as In-111 (for SPECT/CT) or Lu-177 (for radionuclide therapy). After labeling, the preclinical profiles of [111In]In-AAZTA5-LM4 and [177Lu]Lu-AAZTA5-LM4 were compared in HEK293-SST2R cells and double HEK293-SST2R/wtHEK293 tumor-bearing mice using [111In]In-DOTA-LM3 and [177Lu]Lu-DOTA-LM3 as references. The biodistribution of [177Lu]Lu-AAZTA5-LM4 was additionally studied for the first time in a NET patient. Both [111In]In-AAZTA5-LM4 and [177Lu]Lu-AAZTA5-LM4 displayed high and selective targeting of the HEK293-SST2R tumors in mice and fast background clearance via the kidneys and the urinary system. This pattern was reproduced for [177Lu]Lu-AAZTA5-LM4 in the patient according to SPECT/CT results in a monitoring time span of 4–72 h pi. In view of the above, we may conclude that [177Lu]Lu-AAZTA5-LM4 shows promise as a therapeutic radiopharmaceutical candidate for SST2R-expressing human NETs, based on previous [68Ga]Ga-DATA5m-LM4 PET/CT, but further studies are needed to fully assess its clinical value. Furthermore, [111In]In-AAZTA5-LM4 SPECT/CT may represent a legitimate alternative diagnostic option in cases where PET/CT is not available. Full article
(This article belongs to the Special Issue Recent Advances in Radiopharmaceutics, 2nd Edition)
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9 pages, 641 KiB  
Article
Biological Distribution after Oral Administration of Radioiodine-Labeled Acetaminophen to Estimate Gastrointestinal Absorption Function via OATPs, OATs, and/or MRPs
by Kakeru Sato, Asuka Mizutani, Yuka Muranaka, Jianwei Yao, Masato Kobayashi, Kana Yamazaki, Ryuichi Nishii, Kodai Nishi, Takeo Nakanishi, Ikumi Tamai and Keiichi Kawai
Pharmaceutics 2023, 15(2), 497; https://doi.org/10.3390/pharmaceutics15020497 - 02 Feb 2023
Cited by 1 | Viewed by 1437
Abstract
We evaluated the whole-body distribution of orally-administered radioiodine-125 labeled acetaminophen (125I-AP) to estimate gastrointestinal absorption of anionic drugs. 125I-AP was added to human embryonic kidney (HEK)293 and Flp293 cells expressing human organic anion transporting polypeptide (OATP)1B1/3, OATP2B1, organic anion transporter [...] Read more.
We evaluated the whole-body distribution of orally-administered radioiodine-125 labeled acetaminophen (125I-AP) to estimate gastrointestinal absorption of anionic drugs. 125I-AP was added to human embryonic kidney (HEK)293 and Flp293 cells expressing human organic anion transporting polypeptide (OATP)1B1/3, OATP2B1, organic anion transporter (OAT)1/2/3, or carnitine/organic cation transporter (OCTN)2, with and without bromosulfalein (OATP and multidrug resistance-associated protein (MRP) inhibitor) and probenecid (OAT and MRP inhibitor). The biological distribution in mice was determined by oral administration of 125I-AP with and without bromosulfalein and by intravenous administration of 125I-AP. The uptake of 125I-AP was significantly higher in HEK293/OATP1B1, OATP1B3, OATP2B1, OAT1, and OAT2 cells than that in mock cells. Bromosulfalein and probenecid inhibited OATP- and OAT-mediated uptake, respectively. Moreover, 125I-AP was easily excreted in the urine when administered intravenously. The accumulation of 125I-AP was significantly lower in the blood and urinary bladder of mice receiving oral administration of both 125I-AP and bromosulfalein than those receiving only 125I-AP, but significantly higher in the small intestine due to inhibition of OATPs and/or MRPs. This study indicates that whole-body distribution after oral 125I-AP administration can be used to estimate gastrointestinal absorption in the small intestine via OATPs, OATs, and/or MRPs by measuring radioactivity in the urinary bladder. Full article
(This article belongs to the Special Issue Recent Advances in Radiopharmaceutics, 2nd Edition)
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Review

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34 pages, 6421 KiB  
Review
Recent Developments in PET and SPECT Radiotracers as Radiopharmaceuticals for Hypoxia Tumors
by Anh Thu Nguyen and Hee-Kwon Kim
Pharmaceutics 2023, 15(7), 1840; https://doi.org/10.3390/pharmaceutics15071840 - 27 Jun 2023
Cited by 2 | Viewed by 1581
Abstract
Hypoxia, a deficiency in the levels of oxygen, is a common feature of most solid tumors and induces many characteristics of cancer. Hypoxia is associated with metastases and strong resistance to radio- and chemotherapy, and can decrease the accuracy of cancer prognosis. Non-invasive [...] Read more.
Hypoxia, a deficiency in the levels of oxygen, is a common feature of most solid tumors and induces many characteristics of cancer. Hypoxia is associated with metastases and strong resistance to radio- and chemotherapy, and can decrease the accuracy of cancer prognosis. Non-invasive imaging methods such as positron emission tomography (PET) and single-photon emission computed tomography (SPECT) using hypoxia-targeting radiopharmaceuticals have been used for the detection and therapy of tumor hypoxia. Nitroimidazoles are bioreducible moieties that can be selectively reduced under hypoxic conditions covalently bind to intracellular macromolecules, and are trapped within hypoxic cells and tissues. Recently, there has been a strong motivation to develop PET and SPECT radiotracers as radiopharmaceuticals containing nitroimidazole moieties for the visualization and treatment of hypoxic tumors. In this review, we summarize the development of some novel PET and SPECT radiotracers as radiopharmaceuticals containing nitroimidazoles, as well as their physicochemical properties, in vitro cellular uptake values, in vivo biodistribution, and PET/SPECT imaging results. Full article
(This article belongs to the Special Issue Recent Advances in Radiopharmaceutics, 2nd Edition)
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