Development of Novel PET Imaging Agents for Vesicular Monoamine Transporter Type 2

1036 Objectives In August 2008, racemic tetrabenazine (3-(2-methylpropyl)-9,10-dimethoxy- 1,3,4,6,7,11b-hexahydro-2H-benzo[α]quinolizin-2-one, tetrabenazine, (±)-TBZ) was approved for the treatment of chorea associated with Huntington’s disease in USA. The primary pharmacological action of TBZ and its active metabolites is to deplete the levels of monoamines (e.g. dopamine, serotonin, and norepinephrine) within the central nervous system by inhibiting the vesicular monoamine transporter type 2 (VMAT2). (+)-TBZ is the active enantiomer of TBZ and 9-[11C]-(+)-dihydrotetrabenazine (9-[11C]-(+)-DTBZ) has been demonstrated as a useful positron emission tomography (PET) imaging agent in various neurodegenerative disorders. Recently, (+)-10-demethyl-DTBZ, a potential metabolite of (+)-DTBZ, was found to possess similar biding affinity for VMAT2 and could penetrate the blood-brain barrier. In this study, 9-[11C]-(+)-DTBZ and 10-[11C]-(+)-DTBZ were compared for the development of novel potential PET tracers for VMAT2. Methods [11C]CO2 was produced by 14N(p,α)11C reaction in a PETtrace cyclotron and was transferred into TracerLab FXc module for producing [11C]CH4 via H2(g)/Ni reduction. Followed by gas halogenations of [11C]CH4, [11C]CH3I was obtained and was trapped in a vessel containing the precursors, (+)-9-demethyl-DTBZ or (+)-10-demethyl-DTBZ. After labeling, semi-preparative HPLC was performed to purify the labeled product. Afterward a series of quality control tests were performed for 9-[11C]-(+)-DTBZ and 10-[11C]-(+)-DTBZ, respectively. SD rat and an eXplore Vista-DR (GE) small animal PET scanner were used for the experiments. Summation images from 0 to 90 min after 9-[11C]-(+)-DTBZ or 10-[11C]-(+)-DTBZ injection (0.8-1.3 mCi). Volumes of interest were placed on multiple brain areas using PMOD image analysis software with reference to the stereotaxic rat brain atlas. Results 10-[11C]-(+)-DTBZ was radiosynthesized from (+)-10-demethyl-DTBZ and [11C]-CH3I, and the in vivo pharmacokinetic properties and imaging quality of 9-[11C]-(+)-DTBZ and 10-[11C]-(+)-DTBZ were compared. MicroPET studies demonstrated that 10-[11C]-(+)-DTBZ showed high brain uptake and high affinity and specificity for brain VMAT2. Conclusions Further studies of these compounds as potential imaging agents for VMAT2 are currently in progress. $$graphic_64827398-481A-4D76-A88C-C60E6A444CEF$$