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

Waterhouse, Rikki N.; Chang, Raymond C.; Zhao, Jun; Carambot, Patty E.

doi:10.1016/j.nucmedbio.2005.10.007

« Previous Next »Nuclear Medicine and Biology
Volume 33, Issue 2 , Pages 211-215, February 2006

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

Rikki N. Waterhouse
- Department of Psychiatry, Columbia University, New York, NY 10032, USA
- Department of Radiology, Columbia University, New York, NY 10032, USA
- Neurobiology and Imaging Program, Department of Biological Psychiatry, New York State Psychiatric Institute, New York, NY 10032, USA
- Corresponding author. Neurobiology and Imaging Program, Department of Biological Psychiatry, New York State Psychiatric Institute, New York, NY 10032, USA. Tel.: +1 212 543 6630; fax: +1 212 543 6030.
Raymond C. Chang
- Department of Psychiatry, Columbia University, New York, NY 10032, USA
- Neurobiology and Imaging Program, Department of Biological Psychiatry, New York State Psychiatric Institute, New York, NY 10032, USA
Jun Zhao
- Department of Psychiatry, Columbia University, New York, NY 10032, USA
- Neurobiology and Imaging Program, Department of Biological Psychiatry, New York State Psychiatric Institute, New York, NY 10032, USA
Patty E. Carambot
- Department of Psychiatry, Columbia University, New York, NY 10032, USA
- Neurobiology and Imaging Program, Department of Biological Psychiatry, New York State Psychiatric Institute, New York, NY 10032, USA

Received 22 June 2005; received in revised form 19 October 2005; accepted 19 October 2005.

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 [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.

Methods

[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.

Results

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.

Conclusions

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.

Keywords: Sigma-1 receptor, PET, Radiotracer, Flourine-18