Abstract4‐Phenyl‐1‐(4‐phenylbutyl)piperidine(4‐PPBP) is a very potent ligand for σ (Sigma) receptors. The present study was undertaken to evaluate [3H]4‐PPBPas a radioligand for in vivo labeling of cerebral σ 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 ≥ prefrontal cortex ≥ parietal cortex > hypothalamus > olfactory tubercle ≥ 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 dosedependent 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 σ receptors in brain. © 1995 Wiley‐Liss, Inc.This article is a US Government work and, as such, is in the public domain in the United States of America .