Synthesis and evaluation of optically pure [³H]‐(+)‐pentazocine, a highly potent and selective radioligand for σ receptors

Abstract

Tritium‐labeled (+)‐pentazocine ([ 3 H]‐1b) of specific activity 26.6 Ci/mmol was synthesized in 3 steps starting with (+)‐normetazocine (2) of defined optical purity. [ 3 H]‐1b has been characterized as a highly selective ligand for labeling of σ receptors. Competition data revealed that [ 3 H]‐1b could be displaced from guinea pig brain membrane preparations with a number of commonly used σ receptor ligands. [ 3 H]‐1b exhibited saturable, enantioselective binding with a K d of 5.13±0.97 nM and a B max of 1146±122 fmol/mg protein. Phencyclidine (PCP) displaced [ 3 H]‐1b with low affinity while MK‐801 was inactive, thus indicating insignificant activity at the PCP‐binding site; apomorphine failed to displace [ 3 H]‐1b indicating lack of dopamine receptor cross‐reactivity. Since the affinity of [ 3 H]‐1b is about 6 times that of the two commonly employed σ ligands ((+)‐3‐[ 3 H]PPP and [ 3 H]DTG) and since it is more selective for σ receptors than the benzomorphan [ 3 H]SKF‐10,047, it represents the first example of a highly selective benzomorphan based σ receptor ligand. [ 3 H]‐1b should prove useful for further study of the structure and function of σ receptors.