In vivo measures of dopaminergic radioligands in the rat brain: equilibrium infusion studies.

The application of an equilibrium infusion method for measuring specific in vivo radioligand binding in the conscious rat brain was evaluated for two ligands of the dopaminergic system, (+)-alpha-[(11)C]dihydrotetrabenazine (DTBZ) and d-threo-[(11)C]methylphenidate (MePhen). Both radioligands can be successfully utilized to reach equilibrium distributions in rat brain within 1 h; combinations of tritiated and carbon-11-labeled radiotracers can furthermore be used to obtain simultaneous measures of the neuronal membrane dopamine transporter (using [(3)H]MePhen) and vesicular monoamine transporter (using [(11)C]DTBZ) in the same animal. These studies provided quantitative measures of distribution volume ratios, which represent specific radioligand binding. Stereospecificity of in vivo binding was demonstrated using equilibrium infusions of the low-affinity isomers of each ligand, (-)-alpha-[(11)C]dihydrotetrabenazine (DTBZ) and l-threo-[(11)C]methylphenidate, both of which produced uniform brain distributions and no specific binding. Specific binding of (+)-alpha-[(11)C]dihydrotetrabenazine was blocked by co-infusion of tetrabenazine, but was unaffected by administration of methylphenidate, haloperidol, or apomorphine. Specific binding of d-threo-[(11)C]methylphenidate, conversely, was blocked with unlabeled methylphenidate but not affected by tetrabenazine or the dopamine receptor ligands. Equilibrium measures of in vivo radioligand binding, as utilized in this study, offer a quantitative means to evaluate acute and chronic drug effects on in vivo radioligand binding in the rat brain.

Kilbourn MR ，Sherman PS ，Kuszpit K 《SYNAPSE》

Rapid and differential losses of in vivo dopamine transporter (DAT) and vesicular monoamine transporter (VMAT2) radioligand binding in MPTP-treated mice.

The dose- and time-dependent changes of in vivo radioligand binding to the neuronal membrane dopamine transporter (DAT) and vesicular monoamine transporter type 2 (VMAT2) were examined in mouse brain after MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine) administrations. Regional brain distribution studies were done in male C57BL/6 mice using simultaneous injections of d-threo-[(3)H]methylphenidate (DAT) and (+)-alpha-[(11)C]dihydrotetrabenazine (VMAT2). Single (55 mg/kg i.p. ) or multiple (4 x 10 mg/kg i.p., 1-hour intervals) administration of MPTP caused significant reductions in [(3)H]methylphenidate and [(11)C]dihydrotetrabenazine specific striatal binding, measured 14 days later. The single high dose of MPTP produced greater losses of [(11)C]dihydrotetrabenazine binding than did the multiple MPTP dosing regimen. Using the single high dose of MPTP, changes of in vivo binding of the two radioligands were determined at 1, 3, and 14 days after neurotoxin injection. At 1 day, there are large losses of [(3)H]methylphenidate binding (DAT) but no changes in [(11)C]dihydrotetrabenazine binding to the VMAT2 site in the striatum. At 3 and 14 days, there were >50% losses of binding of both bot radioligands, but significantly (P < 0.001) greater losses of VMAT2 binding of [(11)C]dihydrotetrabenazine. These studies indicate that the losses of the neuronal membrane and vesicular transporters are not always equal, and do not occur in the same time frame, after administration of the neurotoxin MPTP.

Kilbourn MR ，Kuszpit K ，Sherman P 《SYNAPSE》

Differential effects of scopolamine on in vivo binding of dopamine transporter and vesicular monoamine transporter radioligands in rat brain.

Kilbourn MR ，Kemmerer ES ，Desmond TJ ，Sherman PS ，Frey KA ... -  《EXPERIMENTAL NEUROLOGY》

In vitro and in vivo studies of benzisoquinoline ligands for the brain synaptic vesicle monoamine transporter.

Lee LC ，Vander Borght T ，Sherman PS ，Frey KA ，Kilbourn MR ... -  《JOURNAL OF MEDICINAL CHEMISTRY》

Long-term reproducibility of in vivo measures of specific binding of radioligands in rat brain.

Kilbourn MR 《NUCLEAR MEDICINE AND BIOLOGY》