IN-VIVO IMAGING OF THE BRAIN VESICULAR MONOAMINE TRANSPORTER

In the search for an in vivo marker of monoamine nerve terminal integr ity, we investigated methoxytetrabenazine (MTBZ) as a tracer of the br ain synaptic vesicular monoamine transporter (VMAT2). Methods: The bio distribution, metabolism and in vivo specificity of MTBZ binding were first evaluated in rodents and the human dosimetry was estimated. Subs equently, the human brain distribution of VMAT2 binding was determined in normal volunteers following administration of [C-11]MTBZ. Brain re gional time-activity curves were obtained, and parametric transport an d binding images were calculated using arterial blood sampling and a t wo-compartment tracer kinetic model. Results: Regional rat brain local ization of [H-3]MTBZ 15 min postinjection was consistent with the know n monoamine nerve terminal density, which demonstrated the highest act ivity in the striatum, lateral septum, substantia nigra pars compacta, the raphe nuclei and the locus coeruleus. At this time, chromatograph y revealed over 82% of brain activity, but less than 47% of plasma act ivity corresponded to authentic MTBZ. In vivo [C-11]MTBZ binding in th e mouse brain was inhibited by coinjection of excess unlabeled dihydro tetrabenazine. In humans [C-11]MTBZ had high initial brain uptake and rapid clearance from all regions, with longest retention in areas of h igh VMAT2 concentration. Parametric quantification of VMAT2 density re vealed the highest distribution volume in the putamen and caudate with lower values in cerebral cortex acid cerebellum. Conclusion: Carbon-1 1-MTBZ is a suitable ligand for PET quantification of the vesicular mo noamine transporter in the human brain.