In vivo imaging of the brain vesicular monoamine transporter.
In the search for an in vivo marker of monoamine nerve terminal integrity, we investigated methoxytetrabenazine (MTBZ) as a tracer of the brain synaptic vesicular monoamine transporter (VMAT2).


METHODS
The biodistribution, metabolism and in vivo specificity of MTBZ binding were first evaluated in rodents and the human dosimetry was estimated. Subsequently, the human brain distribution of VMAT2 binding was determined in normal volunteers following administration of [11C]MTBZ. Brain regional time-activity curves were obtained, and parametric transport and binding images were calculated using arterial blood sampling and a two-compartment tracer kinetic model.


RESULTS
Regional rat brain localization of [3H]MTBZ 15 min postinjection was consistent with the known monoamine nerve terminal density, which demonstrated the highest activity in the striatum, lateral septum, substantia nigra pars compacta, the raphe nuclei and the locus coeruleus. At this time, chromatography revealed over 82% of brain activity, but less than 47% of plasma activity corresponded to authentic MTBZ. In vivo [11C]MTBZ binding in the mouse brain was inhibited by coinjection of excess unlabeled dihydrotetrabenazine. In humans [11C]MTBZ had high initial brain uptake and rapid clearance from all regions, with longest retention in areas of high VMAT2 concentration. Parametric quantification of VMAT2 density revealed the highest distribution volume in the putamen and caudate with lower values in cerebral cortex and cerebellum.


CONCLUSIONS
Carbon-11-MTBZ is a suitable ligand for PET quantification of the vesicular monoamine transporter in the human brain.
Department of Internal Medicine, University of Michigan, Ann Arbor, USA.
T M
TM
Vander Borght
M R
MR
Kilbourn
R A
RA
Koeppe
J N
JN
DaSilva
J E
JE
Carey
D E
DE
Kuhl
K A
KA
Frey
D000328:Adult; D000818:Animals; D001692:Biological Transport; D001921:Brain / Q000000981:diagnostic imaging*; D001923:Brain Chemistry; D002250:Carbon Radioisotopes; D005260:Female; D006023:Glycoproteins / Q000032:analysis*; D006801:Humans; D008024:Ligands; D008297:Male; D008562:Membrane Glycoproteins; D026901:Membrane Transport Proteins; D051379:Mice; D009479:Neuropeptides; D018377:Neurotransmitter Agents / Q000032:analysis*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013747:Tetrabenazine / Q000031:analogs & derivatives*; D014018:Tissue Distribution; D014055:Tomography, Emission-Computed; D050492:Vesicular Biogenic Amine Transport Proteins; D050493:Vesicular Monoamine Transport Proteins
D002250:Carbon Radioisotopes; D006023:Glycoproteins; D008024:Ligands; D008562:Membrane Glycoproteins; D026901:Membrane Transport Proteins; D009479:Neuropeptides; D018377:Neurotransmitter Agents; C493452:SLC18A2 protein, human; C493453:Slc18a2 protein, mouse; C493454:Slc18a2 protein, rat; D050492:Vesicular Biogenic Amine Transport Proteins; D050493:Vesicular Monoamine Transport Proteins; C084867:5-O-methyldihydrotetrabenazine; D013747:Tetrabenazine