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

• Published in: Bioorganic & medicinal chemistry letters Vol. 30; no. 22
• Main Authors: Qiu, Lin, Du, Lixia, Liang, Qianwa, Hu, Hongzhen, Tu, Zhude
• Format: Journal Article
• Language: English
• Published: OXFORD Elsevier 15.11.2020
• Subjects: Chemistry; Chemistry, Medicinal; Chemistry, Organic; Life Sciences & Biomedicine; Pharmacology & Pharmacy; Physical Sciences; Science & Technology; ACTIVATION; POTENT; CHANNEL; Analogues; TRPV4; Radiosynthesis; THERAPEUTIC TARGET; Biodistribution; PET
• ISSN: 0960-894X; 1464-3405
• DOI: 10.1016/j.bmcl.2020.127573

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.