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Preclinical Acute Toxicity Studies and Dosimetry Estimates of the Novel Sigma-1 Receptor Radiotracer, [18F]SFE

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Abstract

[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.

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Acknowledgments

The preclinical development of [18F]SFE was funded by the National Institutes of Health (1RO1 NS40402), with exception of the toxicology studies. Toxicology studies were entirely funded by the Department of Health and Human Services, National Institutes of Health, National Institute of Mental Health, under contract no. N01MH32001.

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Authors and Affiliations

  1. Neurobiology and Imaging Program, Department of Psychiatry, New York State Psychiatric Institute and Columbia University, New York, NY, USA

    Rikki N. Waterhouse PhD, Jun Zhao, Raymond C. Chang & Jon C. Mirsalis

  2. Department of Radiology, Columbia University, New York, NY, USA

    Rikki N. Waterhouse PhD

  3. Department of Radiology and Radiological Sciences, Vanderbilt University, Nashville, TN, USA

    Michael G. Stabin

  4. SRI, International, Menlo Park, CA, USA

    Hanna Ng & Janice Schindler-Horvat

Authors
  1. Rikki N. Waterhouse PhD
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  2. Jun Zhao
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  3. Michael G. Stabin
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  4. Hanna Ng
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  5. Janice Schindler-Horvat
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  6. Raymond C. Chang
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  7. Jon C. Mirsalis
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Correspondence to Rikki N. Waterhouse PhD.

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Waterhouse, R.N., Zhao, J., Stabin, M.G. et al. Preclinical Acute Toxicity Studies and Dosimetry Estimates of the Novel Sigma-1 Receptor Radiotracer, [18F]SFE. Mol Imaging Biol 8, 284–291 (2006). https://doi.org/10.1007/s11307-006-0056-1

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  • DOI: https://doi.org/10.1007/s11307-006-0056-1

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