TY - JOUR
T1 - Development of a carbon-11 PET radiotracer for imaging TRPC5 in the brain
AU - Yu, Yanbo
AU - Liang, Qianwa
AU - Liu, Hui
AU - Luo, Zonghua
AU - Hu, Hongzheng
AU - Perlmutter, Joel S.
AU - Tu, Zhude
N1 - Funding Information:
This work was supported by the USA National Institutes of Health (NIH) through the National Institute of Neurological Disorders and Stroke, the National Institute on Aging [NS075527 and NS103988], the American Parkinson Disease Association (APDA), the Greater St. Louis Chapter of the APDA and Barnes Jewish Hospital Foundation. We would like to thank William H. Margenau of Washington University Cyclotron Facilities for 11C radioisotope production. We are also grateful to John Hood, Emily Williams, and Darryl Craig for their assistance with the nonhuman primate microPET studies. We appreciate Drs. Jiwei Gu, Lin Qiu, Tangadanchu Vijai Kumar Reddy and Joshi Sumit’s help in the animal study.
Publisher Copyright:
© The Royal Society of Chemistry.
PY - 2019
Y1 - 2019
N2 - The transient receptor potential channel 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) combined 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). The in vitro autoradiography study revealed that [11C]HC608 specifically binds to TRPC5. Moreover, initial in vivo evaluation of [11C]HC608 performed in rodents and the microPET study in the brain of non-human primates further demonstrated that [11C]HC608 was able to penetrate the blood brain barrier and sufficiently accumulate in the brain. These results suggest that [11C]HC608 has the potential to be a PET tracer for imaging TRPC5 in vivo.
AB - The transient receptor potential channel 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) combined 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). The in vitro autoradiography study revealed that [11C]HC608 specifically binds to TRPC5. Moreover, initial in vivo evaluation of [11C]HC608 performed in rodents and the microPET study in the brain of non-human primates further demonstrated that [11C]HC608 was able to penetrate the blood brain barrier and sufficiently accumulate in the brain. These results suggest that [11C]HC608 has the potential to be a PET tracer for imaging TRPC5 in vivo.
UR - http://www.scopus.com/inward/record.url?scp=85066832664&partnerID=8YFLogxK
U2 - 10.1039/c9ob00893d
DO - 10.1039/c9ob00893d
M3 - Article
C2 - 31115430
AN - SCOPUS:85066832664
SN - 1477-0520
VL - 17
SP - 5586
EP - 5594
JO - Organic and Biomolecular Chemistry
JF - Organic and Biomolecular Chemistry
IS - 22
ER -