Preclinical acute toxicity studies and rodent-based dosimetry estimates of the novel sigma-1 receptor radiotracer [ 18F]FPS

• Published in: Nuclear medicine and biology 2003-07, Vol.30 (5), p.555-563
• Main Authors: Waterhouse, Rikki N, Stabin, Michael G, Page, John G
• Format: Article
• Language: English
• Subjects: 1-(Fluoropropyl)-4-[(4-cyanophenoxy)methyl]piperidine; Animals; Biological and medical sciences; Dogs; Dose-Response Relationship, Drug; Dosimetry; Drug Evaluation, Preclinical - methods; Female; Humans; In Vitro Techniques; Leukocyte Count; Medical sciences; Organ Specificity; PET; Piperidines - pharmacology; Piperidines - toxicity; Rabbits; Radiation Dosage; Radiometry - methods; Radiopharmaceuticals - pharmacokinetics; Radiopharmaceuticals - toxicity; Radiotracer; Rats; Seizures - etiology; Sigma receptor; Species Specificity; Tissue Distribution; Toxicity; Toxicity Tests - methods
• ISSN: 0969-8051; 1872-9614
• DOI: 10.1016/S0969-8051(03)00020-9

[ 18F]1-(Fluoropropyl)-4-[(4-cyanophenoxy)methyl]piperidine ([ 18F]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 [ 18F]FPS through PET imaging studies in humans, single organ and whole body radiation adsorbed doses associated with [ 18F]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 [ 18F]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 [ 18F]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 μg 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 [ 18F]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 μg FPS per injection.