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Development of a carbon-11 PET radiotracer for imaging TRPC5 in the brain

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Abstract

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.

Graphical abstract: Development of a carbon-11 PET radiotracer for imaging TRPC5 in the brain

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Publication details

The article was received on 17 Apr 2019, accepted on 09 May 2019 and first published on 09 May 2019


Article type: Paper
DOI: 10.1039/C9OB00893D
Org. Biomol. Chem., 2019, Advance Article

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    Development of a carbon-11 PET radiotracer for imaging TRPC5 in the brain

    Y. Yu, Q. Liang, H. Liu, Z. Luo, H. Hu, J. S. Perlmutter and Z. Tu, Org. Biomol. Chem., 2019, Advance Article , DOI: 10.1039/C9OB00893D

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