Development of a Carbon-11 PET Radiotracer for Imaging TRPC5 in the Brain
The transient receptor potential channels subfamily member 5 (TRPC5) is a calcium permeable cation channel widely expressed in the brain. Accumulating evidence indicates that it plays a crucial role in psychiatric disorders including depression and anxiety. Positron emission tomography (PET) combining with a TRPC5 specific radioligand may provide a unique tool to investigate the functions of TRPC5 in animal disease models to guide drug development targeting TRPC5. To develop a TRPC5 PET radiotracer, the potent TRPC5 inhibitor HC608 was chosen for C-11 radiosynthesis through the N-demethyl amide precursor 7 reacting with [11C]methyl iodide. Under optimized conditions, [11C]HC608 was achieved with good radiochemical yield (25 ± 5%), high chemical and radiochemical purity (>99%), and high specific activity (204-377 GBq µmol-1, decay corrected to the end of bombardment, EOB). In vitro autoradiography study reveals that [11C]HC608 specifically binds to TRPC5. Moreover, initial in vivo evaluation of [11C]HC608 performed in rodents and microPET study in the brain of non-human primates further deomonstrate that [11C]HC608 was able to penetrate the blood brain barrier and sufficiently accumulate in the brain. These results suggest that [11C]HC608 has potential to be a PET tracer for imaging TRPC5 in vivo.
- This article is part of the themed collection: Chemical biology in OBC