5-o-methyldihydrotetrabenazine and dihydrotetrabenazine

Topics: Acetylcholine; Alzheimer Disease; Brain; Carbon Radioisotopes; Carrier Proteins; Humans; Membrane Glycoproteins; Membrane Transport Proteins; Neuromuscular Depolarizing Agents; Neurons; Neuropeptides; Neurotransmitter Agents; Parkinson Disease; Piperidines; Tetrabenazine; Tomography, Emission-Computed; Tomography, Emission-Computed, Single-Photon; Tritium; Vesicular Acetylcholine Transport Proteins; Vesicular Biogenic Amine Transport Proteins; Vesicular Transport Proteins

The recovery of in vivo binding sites for (+/-)-alpha-[11C] methoxytetrabenazine, a radioligand for the monoamine vesicular transporter (VMAT2), was determined in mouse brain at various times following a pharmacological dose of tetrabenazine. Concentrations of in vivo radioligand binding sites progressively increased and had reached control values by 8.5 h, and this recovery was consistent with the pharmacokinetics of the competing drug tetrabenazine and its active metabolite, dihydrotetrabenazine. This study demonstrates a simple experimental protocol of using a single dose of a reversible competing drug and time-dependent measurements of in vivo binding of a radioligand. This protocol is suitable for testing the sensitivity of an in vivo radiotracer for measurement of varying concentrations of in vivo binding sites.

Topics: Adrenergic Uptake Inhibitors; Animals; Binding Sites; Brain; Female; Injections, Intravenous; Mice; Radioligand Assay; Tetrabenazine; Time Factors

Sensitivity to the neurotoxic actions of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) varies greatly among strains of mice. The numbers of vesicular monoamine transporters was examined in various brain regions of MPTP-sensitive (C57BL/6) and MPTP-insensitive (CD-1) mouse strains. In vivo radioligand binding to the vesicular monoamine transporter was studied using [11C]methoxytetrabenazine, and in vitro Bmax values determined using [3H]dihydrotetrabenazine autoradiography. Using either technique, no significant differences between the two strains were seen in the striatal binding of these radioligands to the vesicular monoamine transporter. The in vivo binding of radioligands to this transporter in the striatum was also not gender dependent. The relative resistance of CD-1 mice to the neurotoxic effects of peripheral MPTP administration thus does not appear to be a result of enhanced protection by higher levels of vesicular storage in dopaminergic neurons of the striatum.

Topics: 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; Animals; Autoradiography; Binding Sites; Carbon Radioisotopes; Corpus Striatum; Female; In Vitro Techniques; Male; Membrane Glycoproteins; Membrane Transport Proteins; Mice; Mice, Inbred C57BL; Mice, Inbred Strains; Neuropeptides; Neurotransmitter Agents; Protein Binding; Radioactive Tracers; Radioligand Assay; Tetrabenazine; Tissue Distribution; Tritium; Vesicular Biogenic Amine Transport Proteins; Vesicular Monoamine Transport Proteins

The effects of various dopaminergic drug treatments on the in vivo regional brain distribution of high-affinity radioligands ([11C]dihydrotetrabenazine and [11C]methoxytetrabenazine) for the rat brain vesicular monoamine transporter (VMAT2) were determined. Acute treatments with reserpine (2 mg/kg i.p.), tetrabenazine (10 mg/kg i.v.) or related benzoisoquinolines significantly reduced radiotracer binding in vivo. In contrast, radiotracer distributions remained unchanged after treatments with other dopaminergic drugs, whether given by single injection (haloperidol, 1 mg/kg i.p., pargyline 80 mg/kg), repeatedly (pargyline, 80 mg/kg s.c., 14 days), or by continuous infusion (deprenyl, 10 mg/kg/day, 5 days; L-DOPA methyl ester 100 mg/kg/day, 5 days). Repeated injections of tetrabenazine (5 mg/kg i.p., twice daily, 3 days) did not alter in vivo radioligand binding measured after allowing drug washout from the brain. These studies support the proposal that in vivo PET imaging of VMAT2 radioligands in patients with extrapyramidal movement disorders will not be affected by concurrent use of L-DOPA or deprenyl.

Topics: Animals; Biological Transport; Brain; Carbon Radioisotopes; COS Cells; Dopamine Agents; Drug Interactions; Female; Membrane Glycoproteins; Membrane Transport Proteins; Mice; Mice, Inbred Strains; Neuropeptides; Radioligand Assay; Rats; Rats, Sprague-Dawley; Tetrabenazine; Vesicular Biogenic Amine Transport Proteins; Vesicular Monoamine Transport Proteins