AUTORADIOGRAPHIC IDENTIFICATION AND CHARACTERIZATION OF SIGMA RECEPTORS IN GUINEA-PIG BRAIN USING [H-3] 1(CYCLOPROPYLMETHYL)-4-(2'-(4''-FLUOROPHENYL)-2'-OXOETHYL) PIPERIDINE ([H-3]DUP 734), A NOVEL SIGMA RECEPTOR LIGAND

The psychotomimetic effects of certain cycloalkyls and benzomorphans that interact with sigma receptors has led to the hypothesis that these sites may be important in the etiology of schizophrenia. DuP 734 [1-(cyclopropylmethyl)-4-(2'-(4''-fluoro-phenyl)-2'-oxoethyl) piperidine HBr] is a novel sigma receptor ligand. The receptor binding specificity and neuroanatomical distribution of [H-3]DuP 734-labeled sigma receptors in guinea pig brain were examined using quantitative autoradiography. [H-3]DuP 734 binding (10 muM haloperidol displaceable) to slide-mounted sections of guinea pig brain was saturable and of high affinity (K(i) = 3.9 nM). Competition studies, under conditions identical to those used to visualize the receptor, yielded the following rank order of potency: DuP 734 > haloperidol > (+)-pentazocine > (-)-butaclamol > DTG > (+)-SKF 10,047 > (+)-3-PPP > (-)-pentazocine > (+)-butaclamol > U50,488H > (-)-SKF 10,047 > cinanserin > PCP >> MK801, sulpiride. High densities of [H-3]DuP 734 binding sites displaceable by haloperidol were present in the limbic system, in particular the dorsal and ventral bands of Broca as well as the ventral pallidum. Within the hippocampus, the pyramidal layers were sparsely labeled, while higher densities of binding sites were evident in the dentate gyrus. The frontal cortex, the mammillary complex of the hypothalamus, the central gray and red nucleus of the midbrain, the pontine reticular nucleus, the Purkinje cell layer of the cerebellum and dorsal and ventral horns, as well as the central gray matter of the spinal cord, all showed enrichments of [H-3]DuP 734 binding sites. Lower levels of binding were present in the other regions of the cerebral cortex including parietal, pyriform, occipital, cingulate cortex, as well as the basal ganglia, and negligible specific binding was present in the white matter tracts. The kinetic and pharmacological characteristics and distribution of [H-3]DuP 734 binding sites in brain are similar to those previously reported for sigma receptors.