In vivo evaluation of [C-11]SA4503 as a PET ligand for mapping CNS sigma(1) receptors

The potential of the C-11-labeled selective sigma(1) receptor ligand 1-(3,4 -dimethoxyphenethyl)-4-(3-phenylpropyl) piperazine ([C-11]SA4503)was evalua ted in vivo as a positron emission tomography (PET) ligand for mapping sigm a(1) receptors in rats. SA4503 is known to have a high affinity (IC50 = 17. 4 nM) and a higher selectivity (sigma(1)/sigma(2) = 103) for the sigma(1) r eceptor. A high and increasing brain uptake of [C-11]SA4503 was found. Pre- , co and postinjection of cold SA4503 significantly decreased uptake of [C- 11]SA4503 in the brain, spleen, heart, lung, and kidney in which sigma rece ptors are present as well as in the skeletal muscle. In the blocking studs with one of four sigma receptor ligands including haloperidol, (+)-pentazoc ine, SA4503, and (-)-pentazocine (in the order of their affinity for sigma( 1) receptor subtype), SA4503 and haloperidol significantly reduced the brai n uptake of [C-11]SA4503 to approximately 30% of the control, but the other two benzomorphans did not. A high specific uptake of [C-11]SA4503 by the b rain was also confirmed by ex vivo autoradiography (ARG) and PET. Ex vivo A RG showed a higher uptake in the vestibular nucleus, temporal cortex, cingu late cortex, inferior colliculus, thalamus, and frontal cortex, and a moder ate uptake in the parietal cortex and caudate putamen. Peripherally, the bl ocking effects of the four ligands depended on their affinity for sigma(1) receptors. No C-11-labeled metabolite was detected in the brain 30 min post injection, whereas approximately 20% of the radioactivity was found as C-11 -labeled metabolites in plasma. These results have demonstrated that the C- 11-labeled sigma(1) receptor ligand [C-11]SA4503 has a potential for mappin g sigma(1) receptors in the central nervous system and peripheral organs. N UCL MED BIOL 27;3:255-261, 2000. (C) 2000 Elsevier Science Inc. All rights reserved.