In vitro and in vivo studies of benzisoquinoline ligands for the brain synaptic vesicle monoamine transporter.
Tetrabenazine is a high-affinity inhibitor of the vesicular monoamine transporter in mammalian brain. As part of a program to develop in vivo imaging agents for these transporters in human brain, a series of 2-alkylated dihydrotetrabenazine ligands was synthesized and evaluated in vitro and in vivo for binding to the brain vesicular monoamine transporter. Additions of organometallic reagents to tetrabenazine produced 2-methyl, 2-ethyl, 2-n-propyl, 2-isopropyl, and 2-isobutyl derivatives of dihydrotetrabenazine. The stereochemistry and conformation of the addition products were thoroughly verified by two-dimensional NMR techniques. All of these alkyl derivatives displayed in vitro affinity for the vesicular monoamine transporter binding site in rat brain using competitive assays with the radioligand [3H]methoxytetrabenazine. Except for the isopropyl derivative, all compounds when tested at 10 mg/kg iv showed an ability to inhibit in vivo accumulation of the radioligand [11C]methoxytetrabenazine in the mouse brain striatum. Derivatives with small alkyl groups (methyl, ethyl) were more effective than those with large groups (propyl, isobutyl). These studies suggest that large groups in the 2-position of the benzisoquinoline structure will significantly diminish both in vitro and in vivo binding of these compounds to the vesicular monoamine transporter.
Lee
L C
LC
Department of Internal Medicine, University of Michigan Medical School, Ann Arbor 48109, USA.
Vander Borght
T
T
Sherman
P S
PS
Frey
K A
KA
Kilbourn
M R
MR
D018759:Adrenergic Uptake Inhibitors / Q000494:pharmacology; D000818:Animals; D001667:Binding, Competitive; D015306:Biogenic Monoamines / Q000378:metabolism*; D001692:Biological Transport / Q000187:drug effects; D001921:Brain / Q000187:drug effects / Q000378:metabolism; D066298:In Vitro Techniques; D008024:Ligands; D009682:Magnetic Resonance Spectroscopy; D008562:Membrane Glycoproteins / Q000378:metabolism*; D026901:Membrane Transport Proteins; D051379:Mice; D008968:Molecular Conformation; D015394:Molecular Structure; D009479:Neuropeptides; D051381:Rats; D013572:Synaptic Vesicles / Q000737:chemistry / Q000378:metabolism*; D013747:Tetrabenazine / Q000031:analogs & derivatives* / Q000037:antagonists & inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D050492:Vesicular Biogenic Amine Transport Proteins; D050493:Vesicular Monoamine Transport Proteins
D018759:Adrenergic Uptake Inhibitors; D015306:Biogenic Monoamines; D008024:Ligands; D008562:Membrane Glycoproteins; D026901:Membrane Transport Proteins; D009479:Neuropeptides; D050492:Vesicular Biogenic Amine Transport Proteins; D050493:Vesicular Monoamine Transport Proteins; C084867:5-O-methyldihydrotetrabenazine; D013747:Tetrabenazine