Sigma Receptors In Brain Research Articles

In vivo labeling of sigma receptors in mouse brain with [3H]4‐phenyl‐1‐(4‐phenylbutyl)piperidine

4-Phenyl-1-(4-phenylbutyl)piperidine (4-PPBP) is a very potent ligand for sigma (Sigma) receptors. The present study was undertaken to evaluate [3H]4-PPBP as a radioligand for in vivo labeling of cerebral sigma receptors. After intravenous administration of [3H]4-PPBP to mice, there is high uptake of radioactivity in the brain. The regional distribution of radioactivity in the brain 2 h after intravenous injection of [3H]4-PPBP parallels the in vitro binding of the radioligand in rat brain (pons/medulla > cerebellum > or = prefrontal cortex > or = parietal cortex > hypothalamus > olfactory tubercle > or = thalamus > hippocampus > striatum). Pretreatment with haloperidol (2 mg/kg) significantly decreases the radioactivity measured in the brain 30-120 min after injection of [3H]4-PPBP. Pretreatment with unlabeled 4-PPBP or ifenprodil also significantly decreases radioactivity in the brain 2 h after injection of [3H]4-PPBP, in a dose-dependent manner. The in vivo binding of [3H]4-PPBP in the brain also is significantly inhibited by SL 82.0715, BMY 14802, 1,3-di-o-tolylguanidine (DTG), and (+)-enantiomers of pentazocine, SKF 10,047, and 3-PPP, but not by the corresponding (-)-enantiomers, consistent with stereoselectivity of inhibition obtained in in vitro binding studies. In contrast, pretreatment with dizocilpine and spiperone does not inhibit in vivo binding of [3H]4-PPBP. The results indicate that [3H]4-PPBP would be a suitable radioligand for in vivo labeling of sigma receptors in brain.

1,3-Di(2-[5-3H]tolyl)guanidine: a selective ligand that labels sigma-type receptors for psychotomimetic opiates and antipsychotic drugs.

Brain sigma-type receptors are thought to mediate hallucinogenic effects of certain benzomorphan opiates in humans. The biochemical characterization of sigma receptors has been difficult because of the lack of potent and selective ligands. We report here the synthesis and characterization of a tritiated, symmetrically substituted guanidine derivative, 1,3-di(2-[5-3H]tolyl)guanidine ([3H]Tol2Gdn), that binds with high affinity to a single population of binding sites in guinea pig brain membrane preparations. The [3H]Tol2Gdn binding site displays stereoselectivity for dextrorotatory optical isomers of benzomorphan opiates known to have sigma-type behavioral effects. Furthermore, the [3H]Tol2Gdn binding site has a high affinity for haloperidol and for phenothiazine antipsychotics, which have antihallucinatory properties in humans. The drug-selectivity profile of [3H]Tol2Gdn binding closely correlates with the drug-selectivity profile of tritiated (+)-3-(3-hydroxyphenyl)-N-(1-propyl)piperidine [+)-[3H]3-PPP) binding to guinea pig brain membrane receptors. (+)-[3H]3-PPP has been proposed to be a selective sigma-receptor ligand [Largent, B. L., Gundlach, A. L. & Snyder, S. H. (1984) Proc. Natl. Acad. Sci. USA 82, 4983-4987]. Receptor autoradiography using [3H]Tol2Gdn on slide-mounted rat and guinea pig brain sections reveals a heterogeneous distribution pattern of enriched binding in limbic and sensorimotor structures of the brain. These results indicate that [3H]Tol2Gdn is a selective ligand for the sigma-site. Availability of this sigma-receptor probe should greatly facilitate the physiological, biochemical, and pharmacological characterization of sigma receptors in brain.