In vivo evaluation in rats of [(18)F]1-(2-fluoroethyl)-4-[(4-cyanophenoxy)methyl]piperidine as a potential radiotracer for PET assessment of CNS sigma-1 receptors.
BACKGROUND
Sigma-1 receptors are expressed throughout the mammalian central nervous system (CNS) and are implicated in several psychiatric disorders, including schizophrenia and depression. We have recently evaluated the high-affinity (K(D)=0.5+/-0.2 nM, log P=2.9) sigma-1 receptor radiotracer [(18)F]1-(3-fluoropropyl)-4-(4-cyanophenoxymethyl)piperidine, [(18)F]FPS, in humans. In contrast to appropriate kinetics exhibited in baboon brain, in the human CNS, [(18)F]FPS does not reach pseudoequilibrium by 4 h, supporting the development of a lower-affinity tracer [Waterhouse RN, Nobler MS, Chang RC, Zhou Y, Morales O, Kuwabara H, et al. First evaluation of the sigma-1 receptor radioligand [(18)F]1-3-fluoropropyl-4-((4-cyanophenoxy)-methyl)piperidine ([(18)F]FPS) in healthy humans. Neuroreceptor Mapping 2004, July 15-18th, Vancouver, BC Canada 2004]. We describe herein the in vivo evaluation in rats of [(18)F]1-(2-fluoroethyl)-4-[(4-cyanophenoxy)methyl]piperidine ([(18)F]SFE) (K(D)=5 nM, log P=2.4), a structurally similar, lower-affinity sigma-1 receptor radioligand.


METHODS
[(18)F]SFE was synthesized (n=4) as previously described in good yield (54+/-6% EOB), high specific activity (2.1+/-0.6 Ci/micromol EOS) and radiochemical purity (98+/-1%) and evaluated in awake adult male rats.


RESULTS
Similar to [(18)F]FPS, regional brain radioactivity concentrations [percentage of injected dose per gram of tissue (%ID/g), 15 min] for [(18)F]SFE were highest in occipital cortex (1.86+/-0.06 %ID/g) and frontal cortex (1.76+/-0.38 %ID/g), and lowest in the hippocampus (1.01+/-0.02%ID/g). Unlike [(18)F]FPS, [(18)F]SFE cleared from the brain with approximately 40% reduction in peak activity over a 90-min period. Metabolite analysis (1 h) revealed that [(18)F]SFE was largely intact in the brain. Blocking studies showed a large degree (>80%) of saturable binding for [(18)F]SFE in discrete brain regions.


CONCLUSIONS
We conclude that [(18)F]SFE exhibits excellent characteristics in vivo and may provide a superior PET radiotracer for human studies due to its faster CNS clearance compared to [(18)F]FPS.
Department of Psychiatry, Columbia University, New York, NY 10032, USA. rnw7@columbia.edu
Rikki N
RN
Waterhouse
Raymond C
RC
Chang
Jun
J
Zhao
Patty E
PE
Carambot
D000818:Animals; D001921:Brain / Q000000981:diagnostic imaging* / Q000378:metabolism*; D004353:Drug Evaluation, Preclinical; D005240:Feasibility Studies; D008297:Male; D008657:Metabolic Clearance Rate; D009928:Organ Specificity; D010880:Piperidines / Q000737:chemistry / Q000493:pharmacokinetics*; D049268:Positron-Emission Tomography / Q000379:methods*; D019275:Radiopharmaceuticals / Q000138:chemical synthesis / Q000493:pharmacokinetics; D051381:Rats; D017207:Rats, Sprague-Dawley; D017480:Receptors, sigma / Q000378:metabolism*; D014018:Tissue Distribution; D000097605:Sigma-1 Receptor
D010880:Piperidines; D019275:Radiopharmaceuticals; D017480:Receptors, sigma; D000097605:Sigma-1 Receptor; C516143:1-(2-fluoroethyl)-4-((4-cyanophenoxy)methyl)piperidine; C106105:1-(3-fluoropropyl)-4-(4-cyanophenoxymethyl)piperidine