x Deuterium substituted D6FPDTBZ (P17-059) as a new VMAT2 imaging agent.

1030 Objectives: Vesicular monoamine transporters 2 (VMAT2) in the brain serve as transporter for packaging monoamine in vesicles inside neurons for normal CNS neurotransmission. Several analogs of DTBZ ([11C]-(+)-DTBZ, dihydrotetrabenazine and [18F]FP-(+)-DTBZ (fluoropropyl-(+)-dihydrotetrabenazine, a.k.a. [18F]AV-133), are used as VMAT2 imaging agents for studying changes in brain function related to monoamine transmission. A deuterated analog of FP(+)DTBZ was prepared and investigated for its ability to target VMAT2 binding sites. Methods: Deuterated [18F]hexadeuterofluoropropyl-(+)-dihydrotetrabenazine, [18F]D6-FP-(+)-DTBZ, [18F]1, was prepared from its corresponding OTs precursor. In vitro binding, in vivo biodistribution and microPET imaging studies in rodents were carried out. Results: A one step radiolabeling reaction led to the desired [18F]D6-FP-(+)-DTBZ, [18F]1, which showed excellent binding affinity to VMAT2 (Ki = 0.32 ± 0.07 nM) comparable to that of FP-(+)-DTBZ (Ki = 0.33 ± 0.02 nM) using [18F]FP-(+)-DTBZ and rat striatum membrane homogenates. In vivo biodistribution in normal rats showed that [18F]1, exhibited excellent initial brain uptake and comparable high ratio of striatum to cerebellum (target/background) at 1 hr after injection (ratio of 6.05 ± 0.43 vs 5.66 ± 0.72 for [18F]FP-(+)-DTBZ vs [18F]1, respectively). MicroPET imaging studies in rats further confirm that the striatum with high VMAT2 concentration was clearly delineated in normal rat brain after iv injection of [18F]1. We observed minor changes of metabolism in rat plasma between these two agents; however, the changes showed little effect on regional brain uptake and retention.Conclusion: The results lend support for using [18F]D6-FP-(+)-DTBZ, [18F]1, as in vivo PET imaging agent for VMAT2 binding in the brain.