In vivo evaluation of [11C]SA4503 as a PET ligand for mapping CNS sigma1 receptors
摘要
The potential of the 11C-labeled selective sigma1 receptor ligand 1-(3,4-dimethoxyphenethyl)-4-(3-phenylpropyl)piperazine ([11C]SA4503) was evaluated in vivo as a positron emission tomography (PET) ligand for mapping sigma1 receptors in rats. SA4503 is known to have a high affinity (IC50 = 17.4 nM) and a higher selectivity (sigma1/sigma2 = 103) for the sigma1 receptor. A high and increasing brain uptake of [11C]SA4503 was found. Pre-, co- and postinjection of cold SA4503 significantly decreased uptake of [11C]SA4503 in the brain, spleen, heart, lung, and kidney in which sigma receptors are present as well as in the skeletal muscle. In the blocking study with one of four sigma receptor ligands including haloperidol, (+)-pentazocine, SA4503, and (−)-pentazocine (in the order of their affinity for sigma1 receptor subtype), SA4503 and haloperidol significantly reduced the brain uptake of [11C]SA4503 to approximately 30%of the control, but the other two benzomorphans did not. A high specific uptake of [11C]SA4503 by the brain was also confirmed by ex vivo autoradiography (ARG) and PET. Ex vivo ARG showed a higher uptake in the vestibular nucleus, temporal cortex, cingulate cortex, inferior colliculus, thalamus, and frontal cortex, and a moderate uptake in the parietal cortex and caudate putamen. Peripherally, the blocking effects of the four ligands depended on their affinity for sigma1 receptors. No 11C-labeled metabolite was detected in the brain 30 min postinjection, whereas approximately 20%of the radioactivity was found as 11C-labeled metabolites in plasma. These results have demonstrated that the 11C-labeled sigma1 receptor ligand [11C]SA4503 has a potential for mapping sigma1 receptors in the central nervous system and peripheral organs.