In vivo evaluation in rats of [ 18F]1-(2-fluoroethyl)-4-[(4-cyanophenoxy)methyl]piperidine as a potential radiotracer for PET assessment of CNS sigma-1 receptors

• Published in: Nuclear medicine and biology 2006-02, Vol.33 (2), p.211-215
• Main Authors: Waterhouse, Rikki N., Chang, Raymond C., Zhao, Jun, Carambot, Patty E.
• Format: Article
• Language: English
• Subjects: Animals; Brain - diagnostic imaging; Brain - metabolism; Drug Evaluation, Preclinical; Feasibility Studies; Flourine-18; Male; Metabolic Clearance Rate; Organ Specificity; PET; Piperidines - chemistry; Piperidines - pharmacokinetics; Positron-Emission Tomography - methods; Radiopharmaceuticals - chemical synthesis; Radiopharmaceuticals - pharmacokinetics; Radiotracer; Rats; Rats, Sprague-Dawley; Receptors, sigma - metabolism; Sigma-1 Receptor; Tissue Distribution
• ISSN: 0969-8051; 1872-9614
• DOI: 10.1016/j.nucmedbio.2005.10.007

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 [ 18F]1-(3-fluoropropyl)-4-(4-cyanophenoxymethyl)piperidine, [ 18F]FPS, in humans. In contrast to appropriate kinetics exhibited in baboon brain, in the human CNS, [ 18F]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 [ 18F]1-3-fluoropropyl-4-((4-cyanophenoxy)-methyl)piperidine ([ 18F]FPS) in healthy humans. Neuroreceptor Mapping 2004, July 15–18th, Vancouver, BC Canada 2004]. We describe herein the in vivo evaluation in rats of [ 18F]1-(2-fluoroethyl)-4-[(4-cyanophenoxy)methyl]piperidine ([ 18F]SFE) ( K D=5 nM, log P=2.4), a structurally similar, lower-affinity sigma-1 receptor radioligand. [ 18F]SFE was synthesized ( n=4) as previously described in good yield (54±6% EOB), high specific activity (2.1±0.6 Ci/μmol EOS) and radiochemical purity (98±1%) and evaluated in awake adult male rats. Similar to [ 18F]FPS, regional brain radioactivity concentrations [percentage of injected dose per gram of tissue (%ID/g), 15 min] for [ 18F]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 [ 18F]FPS, [ 18F]SFE cleared from the brain with ∼40% reduction in peak activity over a 90-min period. Metabolite analysis (1 h) revealed that [ 18F]SFE was largely intact in the brain. Blocking studies showed a large degree (>80%) of saturable binding for [ 18F]SFE in discrete brain regions. We conclude that [ 18F]SFE exhibits excellent characteristics in vivo and may provide a superior PET radiotracer for human studies due to its faster CNS clearance compared to [ 18F]FPS.