piperidines and 1-(3-fluoropropyl)-4-(4-cyanophenoxymethyl)piperidine

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.

Topics: Animals; Brain; Drug Evaluation, Preclinical; Feasibility Studies; Male; Metabolic Clearance Rate; Organ Specificity; Piperidines; Positron-Emission Tomography; Radiopharmaceuticals; Rats; Rats, Sprague-Dawley; Receptors, sigma; Sigma-1 Receptor; Tissue Distribution

[(18)F]1-(Fluoropropyl)-4-[(4-cyanophenoxy)methyl]piperidine ([(18)F]FPS) is a novel high affinity (KD = 0.5 nM) sigma receptor radioligand that exhibits saturable and selective in vivo binding to sigma receptors in rats, mice and non-human primates. In order to support an IND application for the characterization of [(18)F]FPS through PET imaging studies in humans, single organ and whole body radiation adsorbed doses associated with [(18)F]FPS injection were estimated from distribution data obtained in rats. In addition, acute toxicity studies were conducted in rats and rabbits and limited toxicity analyses were performed in dogs. Radiation dosimetry estimates obtained using rat biodistribution analysis of [(18)F]FPS suggest that most organs would receive around 0.012-0.015 mGy/MBq. The adrenal glands, brain, kidneys, lungs, and spleen would receive slightly higher doses (0.02-0.03 mGy/MBq). The adrenal glands were identified as the organs receiving the greatest adsorbed radiation dose. The total exposure resulting from a 5 mCi administration of [(18)F]FPS is well below the FDA defined limits for yearly cumulative and per study exposures to research participants. Extended acute toxicity studies in rats and rabbits, and limited acute toxicity studies in beagle dogs suggest at least a 175-fold safety margin in humans at a mass dose limit of 2.8 microg per intravenous injection. This estimate is based on the measured no observable effect doses (in mg/m(2)) in these species. These data support the expectation that [(18)F]FPS will be safe for use in human PET imaging studies at a maximum administration of 5 mCi and a mass dose equal to or less than 2.8 microg FPS per injection.

Topics: Animals; Dogs; Dose-Response Relationship, Drug; Drug Evaluation, Preclinical; Female; Humans; In Vitro Techniques; Leukocyte Count; Organ Specificity; Piperidines; Rabbits; Radiation Dosage; Radiometry; Radiopharmaceuticals; Rats; Seizures; Species Specificity; Tissue Distribution; Toxicity Tests

1-(3-Fluoropropyl)-4-(4-cyanophenoxymethyl)piperidine (1) has been synthesized as a selective high affinity (Ki = 4.3 nM) ligand for sigma-1 receptors (Ki sigma-1/sigma2 = 0.03). The corresponding radioligand, 18F-1, was synthesized via nucleophilic [18F]fluoride displacement from the appropriate N-alkylmesylate precursor. After HPLC purification, 18F-1 was obtained in 56-70% EOB (n = 5) with a specific activity > 74,000 MBq/mumol. In vivo distribution and pharmacological blocking studies using 18F-1 were performed in male Australian Albino Wistar rats. 18F-1 exhibited high brain uptake (2.47 +/- 0.37% ID at 20 min PI) with no significant loss of radioactivity from the brain over the course of the study (4 h). The uptake of radioactivity in the brain, lung, heart, and kidney was reduced significantly by the pre-administration sigma receptor-binding ligands, indicating the in vivo specificity of the ligand. The radiotracer also exhibited high uptake (11.14 +/- 1.99% ID/g) in B16 melanoma tumours in nude mice. The mean tumour/ tissue ratios at 4 h for the blood, muscle, lung and brain were 123.8, 7.2, 2.5 and 2.6, respectively. In view of these results, 18F-1 shows promise for the in vivo tomographic evaluation of sigma receptors.

Topics: Analysis of Variance; Animals; Brain; Chromatography, High Pressure Liquid; Fluorine Radioisotopes; Kidney; Liver; Lung; Male; Melanoma, Experimental; Mice; Mice, Nude; Muscle, Skeletal; Myocardium; Piperidines; Radioligand Assay; Rats; Rats, Wistar; Receptors, sigma; Sigma-1 Receptor; Tissue Distribution; Tomography, Emission-Computed