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Radiolabeled Compounds for Cancer
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Radiolabeled Compounds for Cancer

A special issue of Molecules (ISSN 1420-3049). This special issue belongs to the section "Medicinal Chemistry".

Deadline for manuscript submissions: closed (28 February 2023) | Viewed by 11069

Special Issue Editors

Dr. James M. Kelly

E-Mail Website
Guest Editor
Molecular Imaging Innovations Institute (MI3), Department of Radiology, Weill Cornell Medicine, New York, NY 10065, USA
Interests: radiopharmaceuticals; PET; targeted radioligand therapy; metabolism; cancer; cardiovascular disease
Dr. Alejandro Amor-Coarasa

E-Mail Website
Guest Editor
Department of Radiology, Albert Einstein College of Medicine, Bronx, NY 10461, USA
Interests: radiopharmaceuticals; PET; SPECT; targeted radiotherapy; metabolism; cancer; Alzheimer’s disease; cardiovascular

Special Issue Information

Dear Colleagues,

The use of radioactive materials to treat cancer has been around for decades, but startling advances have been achieved in imaging and therapy over the last 25 years. This has been made possible by the identification of molecular targets whose expression or activity is dramatically different in cancerous cells relative to healthy cells and the discovery of new biochemical pathways that drive cancer progression. With the validation of biomarkers, such as somatostatin receptor 2 (SSTR2), prostate-specific membrane antigen (PSMA), and G-protein coupled receptors (e.g. bombesin), among others, an unprecedented number of compounds have undergone clinical evaluation in cancer patients. Many of these ligands have now entered clinical trials and are poised to transform disease management in the coming years.

The goal of this Special Issue is to highlight radiolabeled compounds for newly emerging targets and biochemical processes in cancer. We expect that the manuscripts accepted for publication in this issue will reflect the diversity of targeting vectors, biochemical probes, and cancer biomarkers that are currently studied. To this end, submissions describing radiolabeled small molecules, peptides, antibodies, and other biomacromolecules used as imaging agents, theranostics, or agents for targeted radioligand therapy are encouraged. By a similar token, we equally encourage submissions on probes that study dynamic processes (e.g., metabolism) and that bind to specific molecular targets. It is hoped that these submissions will provide a snapshot of the cutting-edge radiopharmaceutical sciences research in cancer as well as a roadmap to the development of transformational advances for molecular imaging and therapy.

Dr. James M. Kelly
Dr. Alejandro Amor-Coarasa
Guest Editors

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Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2700 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
  • theranostics
  • targeted radioligand therapy
  • cancer

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Published Papers (4 papers)

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Research

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16 pages, 1824 KiB  
Article
Preclinical Evaluation of a New Series of Albumin-Binding 177Lu-Labeled PSMA-Based Low-Molecular-Weight Radiotherapeutics
by Srikanth Boinapally, Suresh Alati, Zirui Jiang, Yu Yan, Alla Lisok, Rajan Singh, Gabriela Lofland, Il Minn, Robert F. Hobbs, Martin G. Pomper and Sangeeta Ray Banerjee
Molecules 2023, 28(16), 6158; https://doi.org/10.3390/molecules28166158 - 21 Aug 2023
Cited by 6 | Viewed by 2274
Abstract
Prostate-specific membrane antigen (PSMA)-based low-molecular-weight agents using beta(β)-particle-emitting radiopharmaceuticals is a new treatment paradigm for patients with metastatic castration-resistant prostate cancer. Although results have been encouraging, there is a need to improve the tumor residence time of current PSMA-based radiotherapeutics. Albumin-binding moieties have [...] Read more.
Prostate-specific membrane antigen (PSMA)-based low-molecular-weight agents using beta(β)-particle-emitting radiopharmaceuticals is a new treatment paradigm for patients with metastatic castration-resistant prostate cancer. Although results have been encouraging, there is a need to improve the tumor residence time of current PSMA-based radiotherapeutics. Albumin-binding moieties have been used strategically to enhance the tumor uptake and retention of existing PSMA-based investigational agents. Previously, we developed a series of PSMA-based, β-particle-emitting, low-molecular-weight compounds. From this series, 177Lu-L1 was selected as the lead agent because of its reduced off-target radiotoxicity in preclinical studies. The ligand L1 contains a PSMA-targeting Lys-Glu urea moiety with an N-bromobenzyl substituent in the ε-amino group of Lys. Here, we structurally modified 177Lu-L1 to improve tumor targeting using two known albumin-binding moieties, 4-(p-iodophenyl) butyric acid moiety (IPBA) and ibuprofen (IBU), and evaluated the effects of linker length and composition. Six structurally related PSMA-targeting ligands (Alb-L1–Alb-L6) were synthesized based on the structure of 177Lu-L1. The ligands were assessed for in vitro binding affinity and were radiolabeled with 177Lu following standard protocols. All 177Lu-labeled analogs were studied in cell uptake and selected cell efficacy studies. In vivo pharmacokinetics were investigated by conducting tissue biodistribution studies for 177Lu-Alb-L2–177Lu-Alb-L6 (2 h, 24 h, 72 h, and 192 h) in male NSG mice bearing human PSMA+ PC3 PIP and PSMA− PC3 flu xenografts. Preliminary therapeutic ratios of the agents were estimated from the area under the curve (AUC0-192h) of the tumors, blood, and kidney uptake values. Compounds were obtained in >98% radiochemical yields and >99% purity. PSMA inhibition constants (Kis) of the ligands were in the ≤10 nM range. The long-linker-based agents, 177Lu-Alb-L4 and 177Lu-Alb-L5, displayed significantly higher tumor uptake and retention (p < 0.001) than the short-linker-bearing 177Lu-Alb-L2 and 177Lu-Alb-L3 and a long polyethylene glycol (PEG) linker-bearing agent, 177Lu-Alb-L6. The area under the curve (AUC0-192h) of the PSMA+ PC3 PIP tumor uptake of 177Lu-Alb-L4 and 177Lu-Alb-L5 were >4-fold higher than 177Lu-Alb-L2, 177Lu-Alb-L3, and 177Lu-Alb-L6, respectively. Also, the PSMA+ PIP tumor uptake (AUC0-192h) of 177Lu-Alb-L2 and 177Lu-Alb-L3 was ~1.5-fold higher than 177Lu-Alb-L6. However, the lowest blood AUC0-192h and kidney AUC0-192h were associated with 177Lu-Alb-L6 from the series. Consequently, 177Lu-Alb-L6 displayed the highest ratios of AUC(tumor)-to-AUC(blood) and AUC(tumor)-to-AUC(kidney) values from the series. Among the other agents, 177Lu-Alb-L4 demonstrated a nearly similar ratio of AUC(tumor)-to-AUC(blood) as 177Lu-Alb-L6. The tumor-to-blood ratio was the dose-limiting therapeutic ratio for all of the compounds. Conclusions: 177Lu-Alb-L4 and 177Lu-Alb-L6 showed high tumor uptake in PSMA+ tumors and tumor-to-blood ratios. The data suggest that linker length and composition can be modulated to generate an optimized therapeutic agent. Full article
(This article belongs to the Special Issue Radiolabeled Compounds for Cancer)
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14 pages, 2257 KiB  
Article
68Ga-Labeled [Leu13ψThz14]Bombesin(7–14) Derivatives: Promising GRPR-Targeting PET Tracers with Low Pancreas Uptake
by Lei Wang, Zhengxing Zhang, Helen Merkens, Jutta Zeisler, Chengcheng Zhang, Aron Roxin, Ruiyan Tan, François Bénard and Kuo-Shyan Lin
Molecules 2022, 27(12), 3777; https://doi.org/10.3390/molecules27123777 - 11 Jun 2022
Cited by 12 | Viewed by 2281
Abstract
The gastrin-releasing peptide receptor (GRPR) is a G-protein-coupled receptor that is overexpressed in many solid cancers and is a promising target for cancer imaging and therapy. However, high pancreas uptake is a major concern in the application of reported GRPR-targeting radiopharmaceuticals, particularly for [...] Read more.
The gastrin-releasing peptide receptor (GRPR) is a G-protein-coupled receptor that is overexpressed in many solid cancers and is a promising target for cancer imaging and therapy. However, high pancreas uptake is a major concern in the application of reported GRPR-targeting radiopharmaceuticals, particularly for targeted radioligand therapy. To lower pancreas uptake, we explored Ga-complexed TacsBOMB2, TacsBOMB3, TacsBOMB4, TacsBOMB5, and TacsBOMB6 derived from a potent GRPR antagonist sequence, [Leu13ψThz14]Bombesin(7–14), and compared their potential for cancer imaging with [68Ga]Ga-RM2. The Ki(GRPR) values of Ga-TacsBOMB2, Ga-TacsBOMB3, Ga-TacsBOMB4, Ga-TacsBOMB5, Ga-TacsBOMB6, and Ga-RM2 were 7.08 ± 0.65, 4.29 ± 0.46, 458 ± 38.6, 6.09 ± 0.95, 5.12 ± 0.57, and 1.51 ± 0.24 nM, respectively. [68Ga]Ga-TacsBOMB2, [68Ga]Ga-TacsBOMB3, [68Ga]Ga-TacsBOMB5, [68Ga]Ga-TacsBOMB6, and [68Ga]Ga-RM2 clearly show PC-3 tumor xenografts in positron emission tomography (PET) images, while [68Ga]Ga-TacsBOMB5 shows the highest tumor uptake (15.7 ± 2.17 %ID/g) among them. Most importantly, the pancreas uptake values of [68Ga]Ga-TacsBOMB2 (2.81 ± 0.78 %ID/g), [68Ga]Ga-TacsBOMB3 (7.26 ± 1.00 %ID/g), [68Ga]Ga-TacsBOMB5 (1.98 ± 0.10 %ID/g), and [68Ga]Ga-TacsBOMB6 (6.50 ± 0.36 %ID/g) were much lower than the value of [68Ga]Ga-RM2 (41.9 ± 10.1 %ID/g). Among the tested [Leu13ψThz14]Bombesin(7–14) derivatives, [68Ga]Ga-TacsBOMB5 has the highest tumor uptake and tumor-to-background contrast ratios, which is promising for clinical translation to detect GRPR-expressing tumors. Due to the low pancreas uptake of its derivatives, [Leu13ψThz14]Bombesin(7–14) represents a promising pharmacophore for the design of GRPR-targeting radiopharmaceuticals, especially for targeted radioligand therapy application. Full article
(This article belongs to the Special Issue Radiolabeled Compounds for Cancer)
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Review

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21 pages, 4776 KiB  
Review
PET Oncological Radiopharmaceuticals: Current Status and Perspectives
by Mai Lin, Ryan P. Coll, Allison S. Cohen, Dimitra K. Georgiou and Henry Charles Manning
Molecules 2022, 27(20), 6790; https://doi.org/10.3390/molecules27206790 - 11 Oct 2022
Cited by 3 | Viewed by 2639
Abstract
Molecular imaging is the visual representation of biological processes that take place at the cellular or molecular level in living organisms. To date, molecular imaging plays an important role in the transition from conventional medical practice to precision medicine. Among all imaging modalities, [...] Read more.
Molecular imaging is the visual representation of biological processes that take place at the cellular or molecular level in living organisms. To date, molecular imaging plays an important role in the transition from conventional medical practice to precision medicine. Among all imaging modalities, positron emission tomography (PET) has great advantages in sensitivity and the ability to obtain absolute imaging quantification after corrections for photon attenuation and scattering. Due to the ability to label a host of unique molecules of biological interest, including endogenous, naturally occurring substrates and drug-like compounds, the role of PET has been well established in the field of molecular imaging. In this article, we provide an overview of the recent advances in the development of PET radiopharmaceuticals and their clinical applications in oncology. Full article
(This article belongs to the Special Issue Radiolabeled Compounds for Cancer)
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13 pages, 3433 KiB  
Review
Application of Cleavable Linkers to Improve Therapeutic Index of Radioligand Therapies
by Joseph Lau, Hwan Lee, Julie Rousseau, François Bénard and Kuo-Shyan Lin
Molecules 2022, 27(15), 4959; https://doi.org/10.3390/molecules27154959 - 4 Aug 2022
Cited by 6 | Viewed by 3393
Abstract
Radioligand therapy (RLT) is an emergent drug class for cancer treatment. The dose administered to cancer patients is constrained by the radiation exposure to normal tissues to maintain an appropriate therapeutic index. When a radiopharmaceutical or its radiometabolite is retained in the kidneys, [...] Read more.
Radioligand therapy (RLT) is an emergent drug class for cancer treatment. The dose administered to cancer patients is constrained by the radiation exposure to normal tissues to maintain an appropriate therapeutic index. When a radiopharmaceutical or its radiometabolite is retained in the kidneys, radiation dose deposition in the kidneys can become a dose-limiting factor. A good exemplar is [177Lu]Lu-DOTATATE, where patients receive a co-infusion of basic amino acids for nephroprotection. Besides peptides, there are other classes of targeting vectors like antibody fragments, antibody mimetics, peptidomimetics, and small molecules that clear through the renal pathway. In this review, we will review established and emerging strategies that can be used to mitigate radiation-induced nephrotoxicity, with a focus on the development and incorporation of cleavable linkers for radiopharmaceutical designs. Finally, we offer our perspectives on cleavable linkers for RLT, highlighting future areas of research that will help advance the technology. Full article
(This article belongs to the Special Issue Radiolabeled Compounds for Cancer)
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