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.

Abstract

INTRODUCTION:

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.

• Authors: Rikki N Waterhouse, Raymond C Chang, Jun Zhao, Patty E Carambot
• Journal: Nuclear medicine and biology (Nucl Med Biol) Vol. 33 Issue 2 Pg. 211-5 (Feb 2006) ISSN: 0969-8051 [Print] United States
• PMID: 16546675 (Publication Type: Evaluation Study, Journal Article, Research Support, N.I.H., Extramural)

Chemical References

• 1-(2-fluoroethyl)-4-((4-cyanophenoxy)methyl)piperidine
• Piperidines
• Radiopharmaceuticals
• Receptors, sigma
• 1-(3-fluoropropyl)-4-(4-cyanophenoxymethyl)piperidine

Topics

• Animals
• Brain (diagnostic imaging, metabolism)
• 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
• Sigma-1 Receptor