In vivo evaluation of [18F]1-(3-fluoropropyl)-4-(4-cyanophenoxymethyl)piperidine: a selective sigma-1 receptor radioligand for PET.

1-(3-Fluoropropyl)-4-(4-cyanophenoxymethyl)piperidine (1) has been synthesized as a selective high affinity (Ki = 4.3 nM) ligand for sigma-1 receptors (Ki sigma-1/sigma2 = 0.03). The corresponding radioligand, 18F-1, was synthesized via nucleophilic [18F]fluoride displacement from the appropriate N-alkylmesylate precursor. After HPLC purification, 18F-1 was obtained in 56-70% EOB (n = 5) with a specific activity > 74,000 MBq/mumol. In vivo distribution and pharmacological blocking studies using 18F-1 were performed in male Australian Albino Wistar rats. 18F-1 exhibited high brain uptake (2.47 +/- 0.37% ID at 20 min PI) with no significant loss of radioactivity from the brain over the course of the study (4 h). The uptake of radioactivity in the brain, lung, heart, and kidney was reduced significantly by the pre-administration sigma receptor-binding ligands, indicating the in vivo specificity of the ligand. The radiotracer also exhibited high uptake (11.14 +/- 1.99% ID/g) in B16 melanoma tumours in nude mice. The mean tumour/ tissue ratios at 4 h for the blood, muscle, lung and brain were 123.8, 7.2, 2.5 and 2.6, respectively. In view of these results, 18F-1 shows promise for the in vivo tomographic evaluation of sigma receptors.