title: Preclinical acute toxicity studies and dosimetry estimates of the novel sigma-1 receptor radiotracer, [18F]SFE.
abstract: [(18)F]1-(2-Fluoroethyl)-4-[(4-cyanophenoxy)methyl]piperidine ([(18)F]SFE) is a novel, selective, high-affinity sigma-1 receptor radioligand that has been preclinically well characterized in rodents. To support an investigational new drug (IND) application for the first evaluation of [(18)F]SFE in humans, single-organ and whole-body radiation adsorbed doses associated with [(18)F]SFE injection were estimated from rat distribution data. In addition, single- and multiple-dose toxicity studies were conducted in rabbits and in dogs. Multiple-dose toxicity studies in rabbits and single-dose toxicity studies in beagles suggest at least a 100-fold safety margin for humans studies at a mass dose limit of 4.0 mug per intravenous injection, based on the combined no observable adverse effect levels (NOAEL, mg/m(2)) measured in these species. Radiation dosimetry estimates obtained from rat biodistribution analyses of [(18)F]SFE suggest that most tissues would receive about 0.010-0.020 mGy/MBq, while the adrenal glands, brain, bone, liver, lungs, and spleen would receive slightly higher doses (0.024-0.044 mGy/MBq). The adrenal glands were identified as the critical organ, because they received the highest adsorbed radiation dose. The total exposure resulting from a 5 mCi administration of [(18)F]SFE is well below the FDA-defined limits for yearly cumulative and per-study exposures to research participants. These combined results support the expectation that [(18)F]SFE will be safe for use in human positron emission tomography (PET) imaging studies with the administration of 5 mCi and a mass dose equal to or less than 4.0 mug SFE per injection.
authors.affiliation: Neurobiology and Imaging Program, Department of Psychiatry, New York State Psychiatric Institute and Columbia University, New York, NY 10032, USA. rnw7@columbia.edu
authors.forename: Rikki N
authors.initials: RN
authors.lastname: Waterhouse
authors.forename: Jun
authors.initials: J
authors.lastname: Zhao
authors.forename: Michael G
authors.initials: MG
authors.lastname: Stabin
authors.forename: Hanna
authors.initials: H
authors.lastname: Ng
authors.forename: Janice
authors.initials: J
authors.lastname: Schindler-Horvat
authors.forename: Raymond C
authors.initials: RC
authors.lastname: Chang
authors.forename: Jon C
authors.initials: JC
authors.lastname: Mirsalis
mesh_terms: D000818:Animals; D002319:Cardiovascular System / Q000000981:diagnostic imaging / Q000187:drug effects; D004285:Dogs; D004353:Drug Evaluation, Preclinical; D005260:Female; D008297:Male; D020714:Maximum Tolerated Dose; D010880:Piperidines / Q000008:administration & dosage* / Q000009:adverse effects / Q000633:toxicity*; D049268:Positron-Emission Tomography / Q000379:methods; D011817:Rabbits; D011829:Radiation Dosage; D011849:Radioactive Tracers; D017480:Receptors, sigma / Q000378:metabolism*; D014018:Tissue Distribution; D000097605:Sigma-1 Receptor
chemical_list: D010880:Piperidines; D011849:Radioactive Tracers; D017480:Receptors, sigma; D000097605:Sigma-1 Receptor; C516143:1-(2-fluoroethyl)-4-((4-cyanophenoxy)methyl)piperidine; C106105:1-(3-fluoropropyl)-4-(4-cyanophenoxymethyl)piperidine