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.

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.
[(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.
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.
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.
AuthorsRikki N Waterhouse, Raymond C Chang, Jun Zhao, Patty E Carambot
JournalNuclear medicine and biology (Nucl Med Biol) Vol. 33 Issue 2 Pg. 211-5 (Feb 2006) ISSN: 0969-8051 [Print] England
PMID16546675 (Publication Type: Evaluation Studies, Journal Article, Research Support, N.I.H., Extramural)
Chemical References
  • 1-(2-fluoroethyl)-4-((4-cyanophenoxy)methyl)piperidine
  • Piperidines
  • Radiopharmaceuticals
  • Receptors, sigma
  • sigma-1 receptor
  • 1-(3-fluoropropyl)-4-(4-cyanophenoxymethyl)piperidine
  • Animals
  • Brain (metabolism, radionuclide imaging)
  • Drug Evaluation, Preclinical
  • Feasibility Studies
  • Male
  • Metabolic Clearance Rate
  • Organ Specificity
  • Piperidines (chemistry, pharmacokinetics)
  • Positron-Emission Tomography (methods)
  • Radiopharmaceuticals (chemical synthesis, pharmacokinetics)
  • Rats
  • Rats, Sprague-Dawley
  • Receptors, sigma (metabolism)
  • Tissue Distribution

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