This project includes studies of potential ligands for imaging sigma receptors using autoradiography, positron emission tomography (PET) or single photon emission tomography (SPECT). Studies of cerebral metabolism in rats show that d-N-allylnormetazocine, a sigma receptor ligand produces dose-dependent effects, reflecting affinities of the drug for sigma and phencyclidine receptors. This study provides experimental evidence that sigma receptors are linked to functional receptors in brain. Radiolabeled 1-(p-iodophenyl)-3-(1-adamantyl)guanidine (PIPAG) binds selectively and with high affinity to sigma receptors in guinea-pig cerebral membranes. Autoradiographically assayed PIPAG binding in slices of guinea-pig brain parallels that of other sigma ligands, suggesting that further study of this potential SPECT ligand is warranted. Sigma receptors are characterized as sigma-1 or sigma-2 receptors based on the relative potencies of known sigma ligands to compete for binding sites in receptor binding assays. Radiolabeled ifenprodil may label selectively sigma-2 receptors in rat brain at 37 degrees C, as the pharmacological profile of ifenprodil binding is highly correlated with that of sigma-2, but not sigma-1 receptors. A new ligand for in vivo and in vitro labeling of sigma receptors, 4-PPBP, is being developed.
