Preclinical acute toxicity studies and dosimetry estimates of the novel sigma-1 receptor radiotracer, [18F]SFE.

[18F]1-(2-Fluoroethyl)-4-[(4-cyanophenoxy)methyl]piperidine ([18F]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 [18F]SFE in humans, single-organ and whole-body radiation adsorbed doses associated with [18F]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 μg per intravenous injection, based on the combined no observable adverse effect levels (NOAEL, mg/m2) measured in these species. Radiation dosimetry estimates obtained from rat biodistribution analyses of [18F]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 [18F]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 [18F]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 μg SFE per injection.