Preclinical acute toxicity studies and dosimetry estimates of the novel sigma-1 receptor radiotracer [¹⁸F]1-(2-fluoroethyl)-4-[(4-cyanophenoxy)methyl]piperidine, [¹⁸F]SFE

Abstract

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Objectives: Sigma-1 receptors are unique single transmembrane protiens thought to play a role in depression, schizophrenia and cocaine addiction We previously developed the high affinity (KD = 0.5 ± 0.2 nM, log P = 2.8) sigma-1 receptor radiotracer [¹⁸F]2-flouropropyl-[(4-cyanophenoxy)methyl]piperidine ([¹⁸F]FPS) and performed the first brain imaging evaluation of this tracer in healthy humans. In contrast to appropriate kinetics measured in baboon brain (equilibrium was reached by 60-80 min), in the human CNS, [¹⁸F]FPS does not reach equilibrium by 4 hr, supporting the development of a lower affinity tracer. We describe herein the advanced preclinical characterization of a lower affinity (KD = 5 nM, log P = 2.4) but structurally similar sigma-1 receptor tracer, [¹⁸F]SFE).

Methods: In order to support an IND application for the first evaluation of [¹⁸F]SFE in humans, organ radiation adsorbed doses associated with [¹⁸F]SFE administration were determined from rat biodistribution data. In addition, multiple dose acute toxicity studies were conducted in rabbits and in dogs.

Results: Acute toxicity studies in rabbits and in beagle dogs 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 doses (NOAEL, mg/m²) measured in these species. Radiation dose estimates obtained from rat biodistribution analyses of [¹⁸F]SFE suggest that most tissues would receive around 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. 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.

Conclusions: These combined results support the expectation that [¹⁸F]SFE will be safe for use in human PET imaging studies with the administration of 5-10 mCi and a mass dose equal to or less than 4.0 µg SFE per injection.

Research Support (if any): NIMH 1R01 NS40402