Novel CDK19-Targeted Radiotracers: A Potential Design Strategy to Improve the Pharmacokinetics and Tumor Uptake

Journal of Medicinal Chemistry, Journal Year: 2024, Volume and Issue: 67(8), P. 6726 - 6737

Published: April 3, 2024

Cyclin-dependent kinase 19 (CDK19) is overexpressed in prostate cancer, making it an attractive target for both imaging and therapy. Since little known about the optimized approach radioligands of nuclear proteins, linker optimization strategies were used to improve pharmacokinetics tumor absorption, including adjustment length, flexibility/rigidity, hydrophilicity/lipophilicity linkers. Molecular docking was conducted virtual screening followed by IC50 determination. Both BALB/c mice P-16 xenografts tissue distribution PET/CT imaging. The ligand 68Ga-10c demonstrated high absorption 5 min after injection sustains long-term within 3 h. Furthermore, exhibited slow clearance predominantly metabolized liver kidneys, showing potential alleviate metabolic pressure enhance safety. Therefore, strategy well suited CDK19 provides a reference radioactive ligands other targets.

Language: Английский

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Design, Synthesis, and Evaluation of [¹⁸F]BIBD-300 as a Positron Emission Tomography Tracer for Poly(ADP-Ribose) Polymerase-1

Molecular Pharmaceutics, Journal Year: 2024, Volume and Issue: 21(5), P. 2606 - 2621

Published: April 12, 2024

Compounds 8a–j were designed to adjust the mode of interaction and lipophilicity FTT by scaffold hopping changing length alkoxy groups. 8a, 8d, 8g, BIBD-300 screened for high-affinity PARP-1 through enzyme inhibition assays are worthy further evaluation. PET imaging MCF-7 subcutaneous tumors with moderate expression showed that compared [18F]FTT, [18F]8a, [18F]8d, [18F]8g exhibited greater nonspecific uptake, a lower target-to-nontarget ratio, severe defluorination, while [18F]BIBD-300 uptake ratio. 22Rv1 tumors, which highly express PARP-1, confirmed in normal organs, such as liver, muscle, bone, was than ratio tumor-to-muscle tumor-to-liver [18F]FTT. The biodistribution results mice validated imaging. Unlike mainly relies on hepatobiliary clearance, [18F]BIBD-300, has lipophilicity, undergoes partial shift from renal providing possibility indicate liver cancer. difference [18F]8j corresponding molecular docking subtle structural modifications greatly optimize properties tracer. Cell experiments also demonstrated high affinity PARP-1. Metabolized unmetabolized [18F]FTT detected brain, indicating they could not accurately quantify amount brain. However, glioma both localize situ C6 U87MG tumors. Based its potential advantages diagnosis breast cancer, prostate glioma, well is new option an excellent

Language: Английский

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Preparation and Evaluation of a Novel ^99mTc-Labeled Niraparib Isonitrile Complex as a Potential PARP-1 Imaging Agent

Molecular Pharmaceutics, Journal Year: 2024, Volume and Issue: 21(7), P. 3321 - 3329

Published: June 6, 2024

Poly ADP-ribose polymerase (PARP) plays an important role in the DNA repair process and has become attractive target for cancer therapy recent years. Given that niraparib good clinical efficacy as a PARP inhibitor, this study aimed to develop radiolabeled derivatives tumor imaging detect expression improve accuracy of stratified patient therapy. The isonitrile derivative (CNPN) was designed, synthesized, obtain [99mTc]Tc-CNPN complex with high radiochemical purity (>95%). It lipophilic stable vitro. In HeLa cell experiments, uptake effectively inhibited by ligand CNPN, indicating binding affinity PARP. According biodistribution studies tumor-bearing mice, moderate can be inhibited, demonstrating its specificity targeting SPECT results showed had at 2 h postinjection. All indicated is promising agent targets

Language: Английский

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[18F]F-Poly(ADP-Ribose) Polymerase Inhibitor Radiotracers for Imaging PARP Expression and Their Potential Clinical Applications in Oncology

Journal of Clinical Medicine, Journal Year: 2024, Volume and Issue: 13(12), P. 3426 - 3426

Published: June 11, 2024

Including poly(ADP-ribose) polymerase (PARP) inhibitors in managing patients with inoperable tumors has significantly improved outcomes. The PARP hamper single-strand deoxyribonucleic acid (DNA) repair by trapping poly(ADP-ribose)polymerase at sites of DNA damage, forming a non-functional "PARP enzyme-inhibitor complex" leading to cell cytotoxicity. effect is more pronounced the presence upregulation and homologous recombination (HR) deficiencies such as breast cancer-associated gene (BRCA1/2). Hence, identifying HR-deficiencies genomic analysis-for instance, BRCA1/2 used triple-negative cancer-should be part selection process for inhibitor therapy. Published data suggest germline mutations do not consistently predict favorable responses inhibitors, suggesting that other factors beyond tumor mutation status may play. A variety factors, including heterogeneity expression intrinsic and/or acquired resistance contributing factors. This justifies use an additional tool appropriate patient selection, which noninvasive, capable assessing whole-body vivo evaluating pharmacokinetics complementary currently available analysis. In this review, we discuss [18F]Fluorine radiotracers their potential imaging pharmacokinetics. To provide context also briefly possible causes or ineffectiveness. discussion focuses on TNBC, type where are standard-of-care treatment strategy.

Language: Английский

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Privileged Scaffolds for Potent and Specific Inhibitors of Mono-ADP-Ribosylating PARPs

Molecules, Journal Year: 2023, Volume and Issue: 28(15), P. 5849 - 5849

Published: Aug. 3, 2023

The identification of new targets to address unmet medical needs, better in a personalized way, is an urgent necessity. introduction PARP1 inhibitors into therapy, almost ten years ago, has represented step forward this need being innovate cancer treatment through precision medicine approach. PARP family consists 17 members which that works by poly-ADP ribosylating the substrate sole enzyme so far exploited as therapeutic target. Most other are mono-ADP-ribosylating (mono-ARTs) enzymes, and recent studies have deciphered their pathophysiological roles appear be very extensive with various potential applications. In parallel, handful mono-ARTs emerged been collected perspective on 2022. After that, additional interesting compounds were identified highlighting hot-topic nature research field prompting update. From present review, where we reported only endowed appropriate profile pharmacological tools or drug candidate, four privileged scaffolds clearly stood out constitute basis for further discovery campaigns.

Language: Английский

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Recent Advances in Radiotracers Targeting Novel Cancer-Specific Biomarkers in China: A Brief Overview

Journal of Nuclear Medicine, Journal Year: 2024, Volume and Issue: 65(Supplement 1), P. 38S - 45S

Published: May 1, 2024

Radiopharmaceuticals play a critical role in nuclear medicine, providing novel tools for specifically delivering radioisotopes the diagnosis and treatment of cancers. As starting point developing radiopharmaceuticals, cancer-specific biomarkers are important receive worldwide attention. This field China is currently experiencing rapid expansion, with multiple radiotracers targeting targets being developed translated into clinical studies. review provides brief overview exploration imaging targets, preclinical evaluation their ligands, translational research from 2020 to 2023, detecting cancer, guiding targeted therapy, visualizing immune microenvironment. We believe that will an even more development medicine world future.

Language: Английский

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Molecular imaging of PARP in cancer: state-of-the-art

Expert Review of Molecular Diagnostics, Journal Year: 2023, Volume and Issue: 23(12), P. 1167 - 1174

Published: Nov. 27, 2023

Introduction Poly-ADP-ribose-polymerase inhibitors (PARPi), which exploit the processes of so-called 'synthetic lethality,' have been successfully implemented in oncological practice. However, not all patients respond to PARPi, and there is an unmet need for noninvasive biomarkers suitable patient selection monitoring during PARPi therapy.

Language: Английский

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PARP inhibitor resistance mechanisms and PARP inhibitor derived imaging probes

Expert Review of Anticancer Therapy, Journal Year: 2024, Volume and Issue: 24(10), P. 989 - 1008

Published: Aug. 29, 2024

Poly(ADP-ribose) polymerase 1 (PARP1) inhibition has become a major target in anticancer therapy. While PARP inhibitors (PARPi) are approved for homologous recombination (HR) deficient cancers, therapeutic resistance is challenge and PARPi now being investigated cancers lacking HR deficiencies. This creates need to develop molecular imaging biomarkers of response improve patient selection circumvent resistance. PubMed clinicaltrials.gov were queried studies on imaging. review summarizes established emerging mechanisms PARPi, the current state theragnostic probes including fluorescently labeled radiolabeled probes. progress been made understanding resistance, clinical evidence remains relatively little known regarding outside Continued research will clarify importance cohorts broader utility PARPi. Progress also imaging, particularly with probes, both have reached validation. Reducing abdominal background signal from probe clearance broaden their applicability, improvements synthesis radiation delivery increase utility.

Language: Английский

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Poly(ADP-ribose) polymerase (PARP)-targeted PET imaging in non-oncology application: a pilot study in preclinical models of nonalcoholic steatohepatitis

American Journal of Nuclear Medicine and Molecular Imaging, Journal Year: 2024, Volume and Issue: 14(1), P. 41 - 47

Published: Jan. 1, 2024

Language: Английский

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Synthesis, Radiolabeling, and Biodistribution Study of a Novel DOTA-Peptide for Targeting Vascular Endothelial Growth Factor Receptors in the Molecular Imaging of Breast Cancer

Pharmaceutics, Journal Year: 2024, Volume and Issue: 16(7), P. 899 - 899

Published: July 4, 2024

As angiogenesis plays a pivotal role in tumor progression and metastasis, leading to more cancer-related deaths, the angiogenic process can be considered as target for diagnostic therapeutic applications. The vascular endothelial growth factor receptor-1 (VEGR-1) VEGFR-2 have high expression on breast cancer cells contribute development. Thus, early diagnosis through VEGFR-1/2 detection is an excellent strategy that significantly increase patient's chance of survival. In this study, VEGFR1/2-targeting peptide VGB3 was conjugated with 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA), using 6-aminohexanoic (Ahx) spacer prevent steric hindrance binding. DOTA-Ahx-VGB3 radiolabeled Gallium-68 (

Language: Английский

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