Synthesis and Characterization of a Specific Iodine‐125‐Labeled TRPC5 Radioligand

Abstract

The nonselective Ca 2 +-permeable transient receptor potential channel subfamily member 5 (TRPC5) belongs to the transient receptor potential canonical (TRPC) superfamily and is widely expressed in the brain. Compelling evidence reveals that TRPC5 plays crucial roles in depression and other psychiatric disorders. To develop a TRPC5 radioligand, following up on our previous effort, we synthesized the iodine compound TZ66127 and its iodine-125-labeled counterpart [ 125 I]TZ66127. The synthesis of TZ66127 was achieved by replacing chloride with iodide in the structure of HC608, and the [ 125 I]TZ66127 was radiosynthesized using its corresponding tributylstannylated precursor. We established a stable human TRPC5-overexpressed HEK293-hTRPC5 cell line and performed Ca 2 + imaging and a cell-binding assay study of TZ66127; these indicated that TZ66127 had good inhibition activity for TRPC5, and the inhibitory efficiency of TZ66127 toward TRPC5 presented in a dose-dependent manner. An in vitro autoradiography and immunohistochemistry study of rat brain sections suggested that [ 125 I]TZ66127 had binding specificity toward TRPC5. Altogether, [ 125 I]TZ66127 has high potential to serve as a radioligand for screening the binding activity of other new compounds toward TRPC5. The availability of [ 125 I]TZ66127 might facilitate the development of therapeutic drugs and PET imaging agents that target TRPC5.

Pharmacology of TRPC Channels and Its Potential in Cardiovascular and Metabolic Medicine

“…Bauer et al used a competitive photoaffinity labelling approach to demonstrate that the effect of xanthines such as Pico145 on TRPC5 channels is mediated by a direct binding interaction (65), and subsequent cryo-EM studies revealed the TRPC5 binding site and mode of Pico145 (see below) (66). In addition, Yu et al reported the development of a Pico145-based 11 C and 125 I radiotracers (67,68). Just et al reported the anxiolytic and antidepressant effects in mice of a close analogue of Pico145, named HC-070 (64).…”