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
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.