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

Abstract

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