Open AccessSynthesis 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
Author(s) -
Filomena Mattner,
Andrew Katsifis,
Thomas Bourdier,
Christian Loc’h,
Paula Berghofer,
Christopher J. R. Fookes,
Tzong-Tyng Hung,
Timothy Jackson,
David Henderson,
Tien Pham,
Brendan J Lee,
Rachael Shepherd,
Ivan Greguric,
Naomi Wyatt,
Thanh Van Le,
Jackson Poon,
Carl Power,
Michael Fulham
Publication year - 2021
Publication title -
rsc medicinal chemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.754
H-Index - 55
ISSN - 2632-8682
DOI - 10.1039/d1md00035g
Subject(s) - translocator protein , biodistribution , ligand (biochemistry) , chemistry , microbiology and biotechnology , single nucleotide polymorphism , radiochemistry , biology , receptor , biochemistry , gene , in vitro , genotype , immunology , neuroinflammation , inflammation
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. [ 18 F]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 [ 18 F]PBR316 in organs known to express TSPO such as heart (3.9%) and adrenal glands (7.5% ID per g) at 1 h. [ 18 F]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. [ 18 F]PBR316 shows in vitro binding that is insensitive to human polymorphism and has specific and selective in vivo binding to the TSPO. [ 18 F]PBR316 is suitable for further biological and clinical studies.