Non-amine dopamine transporter probe [H-3]tropoxene distributes to dopamine-rich regions of monkey brain

Citation
R. De La Garza et al., Non-amine dopamine transporter probe [H-3]tropoxene distributes to dopamine-rich regions of monkey brain, SYNAPSE, 34(1), 1999, pp. 20-27
Citations number
52
Categorie Soggetti
Neurosciences & Behavoir
Journal title
SYNAPSE
ISSN journal
08874476 → ACNP
Volume
34
Issue
1
Year of publication
1999
Pages
20 - 27
Database
ISI
SICI code
0887-4476(199910)34:1<20:NDTP[D>2.0.ZU;2-#
Abstract
Drug development in psychopharmacology has adhered to the unwritten precept that compounds targeting monoamine transporters must contain an amine nitr ogen in the molecular structure. A series of non-amine-bearing aryloxatropa nes that are potent inhibitors of the dopamine transporter (DAT) challenged this precept. In the present study, we investigated the brain distribution of a selective, high-affinity DAT non-amine, [H-3] tropoxene (2-carbometho xy-3,4dichloro-3-aryl-8-oxabicyclo[3.2.1] octene), which binds to the DAT i n monkey striatum. The autoradiographic distribution of [H-3]tropoxene was conducted in tissue sections of rhesus (Macaca mulatta) monkey brain. Highe st accumulation of the radioligand was detected in the putamen and caudate nucleus, with significant levels also observed in the nucleus accumbens and substantia nigra. Moderate to low levels of [H-3]tropoxene binding were no ted in the hypothalamus, amygdala, ventral tegmental area, and thalamus. Th e distribution of [H-3]tropoxene was restricted to brain regions previously identified as expressing DAT, and the relative densities of [H-3]tropoxene binding sites in various brain regions corresponded to those observed with other selective monoamine radioligands for the DAT. This is the first; rep ort to demonstrate that transporter-selective compounds that bear no amine nitrogen in their structure bind selectively to brain regions rich in the t ransporter. The results support our conclusion that an amine nitrogen is no t necessary for compounds to bind to monoamine transporters and distribute in brain according to the known distribution of transporters. The findings provide further incentives to investigate the pharmacological potential of transport inhibitors lacking an amine nitrogen in the molecular structure. (C) 1999 Wiley-Liss, Inc.