In Vivo Nuclear Molecular Imaging in Drug Development and Pharmacological Research 2023

A special issue of Pharmaceuticals (ISSN 1424-8247). This special issue belongs to the section "Radiopharmaceutical Sciences".

Deadline for manuscript submissions: 20 April 2024 | Viewed by 8088

Special Issue Editors

Nemours Children's Hospital, Delaware, DE 19803, USA
Interests: radiochemistry; nuclear medicine; medicinal chemistry; organic synthesis; molecular imaging
Special Issues, Collections and Topics in MDPI journals

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Co-Guest Editor
Department of Radiology, Wake Forest School of Medicine, Winston-Salem, NC 27157, USA
Interests: PET imaging; nuclear medicine; radiochemistry; organic chemistry; neuroimaging; Alzheimer’s disease

Special Issue Information

Dear Colleagues,

Molecular imaging can provide the real-time noninvasive visualization, characterization, and quantification of biological processes at the molecular level in intact living subjects. Nuclear molecular imaging has been receiving a great deal of attention due to its high sensitivity and noninvasive imaging profile. This unique imaging modality enables scientists to study in vivo functional information that is usually challenging or impossible to evaluate using other imaging techniques such as magnetic resonance imaging (MRI) and computed tomography (CT). Furthermore, radioisotope-labeled imaging agents can detect the onset of abnormalities before any morphological changes. With the emerging use of precision medicine and personalized treatment in patient management, nuclear molecular imaging is at the forefront of the trend in aiding diagnosis, monitoring disease progression, and evaluating therapeutic responses.

This special issue of Pharmaceuticals invites both original research and review articles related to in vivo nuclear imaging in drug development and pharmacological research, and we welcome submissions on the following topics: 1) identification and validation of in vivo biomarkers by nuclear molecular imaging; 2) evaluation of on-target and off-target effects, receptor occupancy, and biodistribution information of the radiotracers; 3) in vivo biorthogonal reaction involving radioisotopes to probe disease mechanisms; 4) determining pharmacokinetics and pharmacodynamics as well as metabolic profiles; 5) dosimetry studies, kinetic modeling of radiotracers in pre-clinical research and clinical investigation; and 6) bench-to-bedside clinical translation of radiotracers.

Dr. Xuyi Yue
Dr. Kiran Kumar Solingapuram Sai
Guest Editors

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Keywords

  • nuclear molecular imaging
  • drug development
  • in vivo application
  • biomarkers
  • nuclear precision medicine

Published Papers (6 papers)

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Research

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13 pages, 1655 KiB  
Article
Radioligand Therapy with [177Lu]Lu-DOTA-TATE or [177Lu]Lu-DOTA-TATE and [90Y]Y-DOTA-TATE in Patients with Neuroendocrine Neoplasms of Unknown Locations, or Locations Other Than the Midgut and Pancreas as Primaries in a G1, G2 and G3 Grade
by Adam Daniel Durma, Marek Saracyn, Maciej Kołodziej, Katarzyna Jóźwik-Plebanek, Beata Dmochowska, Adrianna Mróz, Wawrzyniec Żmudzki and Grzegorz Kamiński
Pharmaceuticals 2023, 16(9), 1205; https://doi.org/10.3390/ph16091205 - 24 Aug 2023
Viewed by 1258
Abstract
Background: Neuroendocrine neoplasms (NENs) are a rare group of tumors with a different clinical course, prognosis and location. Radioligand therapy (RLT) can be used as a first or second line of treatment. It is registered in gastroenteropancreatic NENs (GEP-NENs) as grades G1 and [...] Read more.
Background: Neuroendocrine neoplasms (NENs) are a rare group of tumors with a different clinical course, prognosis and location. Radioligand therapy (RLT) can be used as a first or second line of treatment. It is registered in gastroenteropancreatic NENs (GEP-NENs) as grades G1 and G2. Tumors with an unknown point of origin, diagnosed outside the gastrointestinal tract and pancreas (non-GEP) or at the G3 grade, remain in the “grey area” of treatment. Materials and Methods: Analysis of 51 patients with NENs who underwent RLT in a single highest reference center from 2018 to 2023 was performed. Treatment was administrated to the patients with neoplasms of unknown origin, non-GEP-NENs, and ones with G3 grade. In total, 35 patients received 177-Lutetium (7.4 GBq), while 16 received 177-Lutetium and 90-Yttrium with equal activities (1.85 + 1.85 GBq). Results: The progression-free survival (PFS) before RLT qualification was 34.39 ± 35.88 months for the whole study group. In subgroups of patients with an unknown tumor location (n = 25), the median PFS was 19 months (IQR = 23), with “other” locations (n = 21) at 31 months (IQR = 28), and with NEN G3 (n = 7) at 18 months (IQR = 40). After RLT, disease stabilization or regression was observed in 42 (87.5% of) patients. RLT did not cause statistical changes in creatinine or GFR values. Hematological parameters (RBC, WBC, PLT, HGB) as well as chromogranin A concentration decreased significantly. There were no statistical differences between both subgroups regarding the type of radioisotope (177-Lutetium vs. 177-Lutetium and 90-Yttrium). After RLT in long-term observation, the median observation time (OT) was 14 months (IQR = 18 months). In patients with progression (n = 8), the median PFS was 20 months (IQR = 16 months), while in patients with confirmed death (n = 9), the median overall survival (OS) was 8 months (IQR = 14 months). Conclusions: Our study showed that 87.5% of NEN patients with unknown origin, non-GEP-NENs, and those with GEP-NEN G3 grade had benefited from the radioligand therapy. There were no significantly negative impacts on renal parameters. The decrease of bone marrow parameters was acceptable in relation to beneficial disease course. The decrease of chromogranin concentration was confirmed as a predictive factor for disease stabilization or regression. Full article
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11 pages, 1933 KiB  
Communication
The Glutaminase-1 Inhibitor [11C-carbony]BPTES: Synthesis and Positron Emission Tomography Study in Mice
by Yiding Zhang, Katsushi Kumata, Lin Xie, Yusuke Kurihara, Masanao Ogawa, Tomomi Kokufuta, Nobuki Nengaki and Ming-Rong Zhang
Pharmaceuticals 2023, 16(7), 963; https://doi.org/10.3390/ph16070963 - 05 Jul 2023
Viewed by 1178
Abstract
Bis-2-(5-phenylacetamido-1,3,4-thiadiazol-2-yl)ethyl sulfide (BPTES) is a selective inhibitor of glutaminase-1 (GLS1), consequently inhibiting glutaminolysis. BPTES is known for its potent antitumor activity and plays a significant role in senescent cell removal. In this study, we synthesized [11C-carbonyl]BPTES ([11C]BPTES) as a [...] Read more.
Bis-2-(5-phenylacetamido-1,3,4-thiadiazol-2-yl)ethyl sulfide (BPTES) is a selective inhibitor of glutaminase-1 (GLS1), consequently inhibiting glutaminolysis. BPTES is known for its potent antitumor activity and plays a significant role in senescent cell removal. In this study, we synthesized [11C-carbonyl]BPTES ([11C]BPTES) as a positron emission tomography (PET) probe for the first time and assessed its biodistribution in mice using PET. [11C]BPTES was synthesized by the reaction of an amine precursor () with [11C-carbonyl]phenylacetyl acid anhydride ([11C]2), which was prepared from [11C]CO2 and benzyl magnesium chloride, followed by in situ treatment with isobutyl chloroformate. The decay-corrected isolated radiochemical yield of [11C]BPTES was 9.5% (based on [11C]CO2) during a synthesis time of 40 min. A PET study with [11C]BPTES showed high uptake levels of radioactivity in the liver, kidney, and small intestine of mice. Full article
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17 pages, 5407 KiB  
Article
Demonstration of the Early Cardiac Bioavailability of a Non-Specific Cell-Targeted Peptide Using Radionuclide-Based Imaging In Vivo
by Stephan Settelmeier, Zohreh Varasteh, Magdalena Staniszewska, Anna-Lena Beerlage, Fadi Zarrad, Wolfgang P. Fendler, Christoph Rischpler, Johannes Notni, Matthias Totzeck, Ken Herrmann, Tienush Rassaf and Ulrike B. Hendgen-Cotta
Pharmaceuticals 2023, 16(6), 824; https://doi.org/10.3390/ph16060824 - 31 May 2023
Cited by 1 | Viewed by 1203
Abstract
The cardiac bioavailability of peptide drugs that inhibit harmful intracellular protein–protein interactions in cardiovascular diseases remains a challenging task in drug development. This study investigates whether a non-specific cell-targeted peptide drug is available in a timely manner at its intended biological destination, the [...] Read more.
The cardiac bioavailability of peptide drugs that inhibit harmful intracellular protein–protein interactions in cardiovascular diseases remains a challenging task in drug development. This study investigates whether a non-specific cell-targeted peptide drug is available in a timely manner at its intended biological destination, the heart, using a combined stepwise nuclear molecular imaging approach. An octapeptide (heart8P) was covalently coupled with the trans-activator of transcription (TAT) protein transduction domain residues 48–59 of human immunodeficiency virus-1 (TAT-heart8P) for efficient internalization into mammalian cells. The pharmacokinetics of TAT-heart8P were evaluated in dogs and rats. The cellular internalization of TAT-heart8P-Cy(5.5) was examined on cardiomyocytes. The real-time cardiac delivery of 68Ga-NODAGA-TAT-heart8P was tested in mice under physiological and pathological conditions. Pharmacokinetic studies of TAT-heart8P in dogs and rats revealed a fast blood clearance, high tissue distribution, and high extraction by the liver. TAT-heart-8P-Cy(5.5) was rapidly internalized in mouse and human cardiomyocytes. Correspondingly, organ uptake of hydrophilic 68Ga-NODAGA-TAT-heart8P occurred rapidly after injection with an initial cardiac bioavailability already 10 min post-injection. The saturable cardiac uptake was revailed by the pre-injection of the unlabeled compound. The cardiac uptake of 68Ga-NODAGA-TAT-heart8P did not change in a model of cell membrane toxicity. This study provides a sequential stepwise workflow to evaluate the cardiac delivery of a hydrophilic, non-specific cell-targeting peptide. 68Ga-NODAGA-TAT-heart8P showed rapid accumulation in the target tissue early after injection. The implementation of PET/CT radionuclide-based imaging methodology as a means to assess effective and temporal cardiac uptake represents a useful and critical application in drug development and pharmacological research and can be extended to the evaluation of comparable drug candidates. Full article
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12 pages, 2543 KiB  
Article
In Vivo Imaging and Kinetic Modeling of Novel Glycogen Synthase Kinase-3 Radiotracers [11C]OCM-44 and [18F]OCM-50 in Non-Human Primates
by Kelly Smart, Ming-Qiang Zheng, Daniel Holden, Zachary Felchner, Li Zhang, Yanjiang Han, Jim Ropchan, Richard E. Carson, Neil Vasdev and Yiyun Huang
Pharmaceuticals 2023, 16(2), 194; https://doi.org/10.3390/ph16020194 - 28 Jan 2023
Cited by 2 | Viewed by 1573
Abstract
Glycogen synthase kinase 3 (GSK-3) is a potential therapeutic target for a range of neurodegenerative and psychiatric disorders. The goal of this work was to evaluate two leading GSK-3 positron emission tomography (PET) radioligands, [11C]OCM-44 and [18F]OCM-50, in non-human [...] Read more.
Glycogen synthase kinase 3 (GSK-3) is a potential therapeutic target for a range of neurodegenerative and psychiatric disorders. The goal of this work was to evaluate two leading GSK-3 positron emission tomography (PET) radioligands, [11C]OCM-44 and [18F]OCM-50, in non-human primates to assess their potential for clinical translation. A total of nine PET scans were performed with the two radiotracers using arterial blood sampling in adult rhesus macaques. Brain regional time-activity curves were extracted and fitted with one- and two-tissue compartment models using metabolite-corrected arterial input functions. Target selectivity was assessed after pre-administration of the GSK-3 inhibitor PF-04802367 (PF-367, 0.03–0.25 mg/kg). Both radiotracers showed good brain uptake and distribution throughout grey matter. [11C]OCM-44 had a free fraction in the plasma of 3% at baseline and was metabolized quickly. The [11C]OCM-44 volume of distribution (VT) values in the brain increased with time; VT values from models fitted to truncated 60-min scan data were 1.4–2.9 mL/cm3 across brain regions. The plasma free fraction was 0.6% for [18F]OCM-50 and VT values (120-min) were 0.39–0.87 mL/cm3 in grey matter regions. After correcting for plasma free fraction increases during blocking scans, reductions in regional VT indicated >80% target occupancy by 0.1 mg/kg of PF-367 for both radiotracers, supporting target selectivity in vivo. [11C]OCM-44 and [18F]OCM-50 warrant further evaluation as radioligands for imaging GSK-3 in the brain, though radio-metabolite accumulation may confound image analysis. Full article
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Review

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21 pages, 2681 KiB  
Review
Cardiac PET Imaging of ATP Binding Cassette (ABC) Transporters: Opportunities and Challenges
by Wanling Liu, Pascalle Mossel, Verena Schwach, Riemer H. J. A. Slart and Gert Luurtsema
Pharmaceuticals 2023, 16(12), 1715; https://doi.org/10.3390/ph16121715 - 11 Dec 2023
Viewed by 860
Abstract
Adenosine triphosphate binding cassette (ABC) transporters are a broad family of membrane protein complexes that use energy to transport molecules across cells and/or intracellular organelle lipid membranes. Many drugs used to treat cardiac diseases have an affinity for these transporters. Among others, P-glycoprotein [...] Read more.
Adenosine triphosphate binding cassette (ABC) transporters are a broad family of membrane protein complexes that use energy to transport molecules across cells and/or intracellular organelle lipid membranes. Many drugs used to treat cardiac diseases have an affinity for these transporters. Among others, P-glycoprotein (P-gp) plays an essential role in regulating drug concentrations that reach cardiac tissue and therefore contribute to cardiotoxicity. As a molecular imaging modality, positron emission tomography (PET) has emerged as a viable technique to investigate the function of P-gp in organs and tissues. Using PET imaging to evaluate cardiac P-gp function provides new insights for drug development and improves the precise use of medications. Nevertheless, information in this field is limited. In this review, we aim to examine the current applications of ABC transporter PET imaging and its tracers in the heart, with a specific emphasis on P-gp. Furthermore, the opportunities and challenges in this novel field will be discussed. Full article

Other

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9 pages, 1475 KiB  
Brief Report
Binding Parameters of [11C]MPC-6827, a Microtubule-Imaging PET Radiopharmaceutical in Rodents
by Avinash H. Bansode, Bhuvanachandra Bhoopal, Krishna Kumar Gollapelli, Naresh Damuka, Ivan Krizan, Mack Miller, Suzanne Craft, Akiva Mintz and Kiran Kumar Solingapuram Sai
Pharmaceuticals 2023, 16(4), 495; https://doi.org/10.3390/ph16040495 - 27 Mar 2023
Cited by 2 | Viewed by 1253
Abstract
Impairment and/or destabilization of neuronal microtubules (MTs) resulting from hyper-phosphorylation of the tau proteins is implicated in many pathologies, including Alzheimer’s disease (AD), Parkinson’s disease and other neurological disorders. Increasing scientific evidence indicates that MT-stabilizing agents protect against the deleterious effects of neurodegeneration [...] Read more.
Impairment and/or destabilization of neuronal microtubules (MTs) resulting from hyper-phosphorylation of the tau proteins is implicated in many pathologies, including Alzheimer’s disease (AD), Parkinson’s disease and other neurological disorders. Increasing scientific evidence indicates that MT-stabilizing agents protect against the deleterious effects of neurodegeneration in treating AD. To quantify these protective benefits, we developed the first brain-penetrant PET radiopharmaceutical, [11C]MPC-6827, for in vivo quantification of MTs in rodent and nonhuman primate models of AD. Mechanistic insights revealed from recently reported studies confirm the radiopharmaceutical’s high selectivity for destabilized MTs. To further translate it to clinical settings, its metabolic stability and pharmacokinetic parameters must be determined. Here, we report in vivo plasma and brain metabolism studies establishing the radiopharmaceutical-binding constants of [11C]MPC-6827. Binding constants were extrapolated from autoradiography experiments; pretreatment with a nonradioactive MPC-6827 decreased the brain uptake >70%. It exhibited ideal binding characteristics (typical of a CNS radiopharmaceutical) including LogP (2.9), Kd (15.59 nM), and Bmax (11.86 fmol/mg). Most important, [11C]MPC-6827 showed high serum and metabolic stability (>95%) in rat plasma and brain samples. Full article
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