Synthesis and pharmacological evaluation of [18F]PBR316: a novel PET ligand targeting the translocator protein 18 kDa (TSPO) with low binding sensitivity to human single nucleotide polymorphism rs6971
| Autor: | Tien Pham, Naomi Wyatt, Ivan Greguric, Thanh Le, Michael J. Fulham, Filomena Mattner, Christopher J. R. Fookes, Andrew Katsifis, Timothy Jackson, Christian Loc'h, Tzong-Tyng Hung, Jackson Poon, Brendan Lee, Rachael Shepherd, David Henderson, Carl Power, Thomas Bourdier, Paula Berghofer |
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| Rok vydání: | 2021 |
| Předmět: |
Pharmacology
Biodistribution biology Chemistry Organic Chemistry Neurodegeneration Pharmaceutical Science Metabolism medicine.disease Biochemistry Molecular biology 030218 nuclear medicine & medical imaging 03 medical and health sciences 0302 clinical medicine Flumazenil In vivo Drug Discovery medicine Translocator protein biology.protein Molecular Medicine Receptor 030217 neurology & neurosurgery Neuroinflammation medicine.drug |
| Zdroj: | RSC Medicinal Chemistry. 12:1207-1221 |
| ISSN: | 2632-8682 |
| Popis: | Radiopharmaceuticals that target the translocator protein 18 kDa (TSPO) have been investigated with positron emission tomography (PET) to study neuroinflammation, neurodegeneration and cancer. We have developed the novel, achiral, 2-phenylimidazo[1,2-a]pyridine, PBR316 that targets the translocator protein 18 kDa (TSPO) that addresses some of the limitations inherent in current TSPO ligands; namely specificity in binding, blood brain barrier permeability, metabolism and insensitivity to TSPO binding in subjects as a result of rs6971 polymorphism. PBR316 has high nanomolar affinity (4.7-6.0 nM) for the TSPO, >5000 nM for the central benzodiazepine receptor (CBR) and low sensitivity to rs6971 polymorphism with a low affinity binders (LABs) to high affinity binders (HABs) ratio of 1.5. [18F]PBR316 was prepared in 20 ± 5% radiochemical yield, >99% radiochemical purity and a molar activity of 160-400 GBq μmol-1. Biodistribution in rats showed high uptake of [18F]PBR316 in organs known to express TSPO such as heart (3.9%) and adrenal glands (7.5% ID per g) at 1 h. [18F]PBR316 entered the brain and accumulated in TSPO-expressing regions with an olfactory bulb to brain ratio of 3 at 15 min and 7 at 4 h. Radioactivity was blocked by PK11195 and Ro 5-4864 but not Flumazenil. Metabolite analysis showed that radioactivity in adrenal glands and the brain was predominantly due to the intact radiotracer. PET-CT studies in mouse-bearing prostate tumour xenografts indicated biodistribution similar to rats with radioactivity in the tumour increasing with time. [18F]PBR316 shows in vitro binding that is insensitive to human polymorphism and has specific and selective in vivo binding to the TSPO. [18F]PBR316 is suitable for further biological and clinical studies. |
| Databáze: | OpenAIRE |
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