Amino- and amido-tetrabenazine derivatives: synthesis and evaluation as potential ligands for the vesicular monoamine transporter.
Tetrabenazine (TBZ) and dihydrotetrabenazine are well known inhibitors of the CNS vesicular monoamine transporter (VMAT), which is responsible for the packaging of monoamine neurotransmitters in presynaptic vesicles. Amino and amido derivatives of tetrabenazine were prepared as potential ligands for the vesicular monoamine transporter. Ultimately, organotin derivatives of promising ligands were prepared for radiolabeling with 125I. The compounds were evaluated for their ability to inhibit the specific binding of a selective radioligand to the transporter in rat striatal homogenates. Of the compounds evaluated, three amine derivatives of TBZ (primary, secondary and tertiary) were found to have modest to high affinity for the transporter, while two amides exhibited low to undectable affinity. The secondary propargyl amine was found to possess the highest affinity (Ki = 7.6 nM) and was chosen for further evaluation. The organotin derivative of this compound was synthesized in order to prepare the corresponding radioiodinated ligand. However, our inability to synthesize and characterize the iodinated amine precluded its evaluation as a potential radioiodinated ligand for the transporter. Alternative approaches for decreasing the lipophilicity of TBZ analogs while maintaining high binding affinity are currently being explored.
Canney
D J
DJ
Department of Radiology, University of Pennsylvania, Philadelphia 19104, USA.
Kung
M P
MP
Kung
H F
HF
D000577:Amides; D000588:Amines; D000818:Animals; D002462:Cell Membrane / Q000378:metabolism; D003342:Corpus Striatum / Q000378:metabolism*; D006023:Glycoproteins / Q000032:analysis / Q000378:metabolism*; D007202:Indicators and Reagents; D007457:Iodine Radioisotopes / Q000378:metabolism; D007553:Isotope Labeling / Q000379:methods; D009682:Magnetic Resonance Spectroscopy; D008562:Membrane Glycoproteins; D026901:Membrane Transport Proteins; D015394:Molecular Structure; D009479:Neuropeptides; D018377:Neurotransmitter Agents / Q000378:metabolism; D011869:Radioligand Assay; D051381:Rats; D013747:Tetrabenazine / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000378:metabolism*; D050492:Vesicular Biogenic Amine Transport Proteins; D050493:Vesicular Monoamine Transport Proteins
D000577:Amides; D000588:Amines; D006023:Glycoproteins; D007202:Indicators and Reagents; D007457:Iodine Radioisotopes; D008562:Membrane Glycoproteins; D026901:Membrane Transport Proteins; D009479:Neuropeptides; D018377:Neurotransmitter Agents; D050492:Vesicular Biogenic Amine Transport Proteins; D050493:Vesicular Monoamine Transport Proteins; D013747:Tetrabenazine