Synthesis and in vitro evaluation of new TRPV4 ligands and biodistribution study of an 11C-labeled radiotracer in rodents

[摘要] Nine new compounds targeting the transient receptor potential vanilloid-4 (TRPV4) were synthesized and their biological activities toward TRPV4 were determined using freshly isolated mouse skin macrophages through live cell Ca2+ imaging assay. Three compounds 4b, 4c, and 4i exhibited higher percentages of in vitro activation of TRPV4 as 48.1%, 59.3% and 33.5%, which are comparable to 56.4% activation response of the reported TRPV4 agonist GSK1016790A (3). The compound 4i was chosen for C-11-radiosynthesis using its phenol precursor 4g to reacted with [C-11]methyl iodide. The radiosynthesis was achieved with good radiochemical yield (16 +/- 5%), high chemical and radiochemical purity (> 95%), and high molar activity (16-21 GBq/mu mol, decay corrected to the end of bombardment, EOB n >= 4). Furthermore, the initial ex vivo biodistribution study in rats showed that [C-11]4i had higher uptake in kidney, liver and small intestine compared to other tissues with rapid washout.

[发布日期] 2020-11-15

[关键词] TRPV4;Analogues;PET;Radiosynthesis;Biodistribution