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Shen B, James ML, Andrews L, et al. Further validation to support clinical translation of [(18)F]FTC-146 for imaging sigma-1 receptors. EJNMMI Res. 2015;5(1):49doi: 10.1186/s13550-015-0122-2.
Shen, B., James, M. L., Andrews, L., Lau, C., Chen, S., Palner, M., Miao, Z., Arksey, N. C., Shuhendler, A. J., Scatliffe, S., Kaneshige, K., Parsons, S. M., McCurdy, C. R., Salehi, A., Gambhir, S. S., & Chin, F. T. (2015). Further validation to support clinical translation of [(18)F]FTC-146 for imaging sigma-1 receptors. EJNMMI research, 5(1), 49. https://doi.org/10.1186/s13550-015-0122-2
Shen, Bin, et al. "Further validation to support clinical translation of [(18)F]FTC-146 for imaging sigma-1 receptors." EJNMMI research vol. 5,1 (2015): 49. doi: https://doi.org/10.1186/s13550-015-0122-2
Shen B, James ML, Andrews L, Lau C, Chen S, Palner M, Miao Z, Arksey NC, Shuhendler AJ, Scatliffe S, Kaneshige K, Parsons SM, McCurdy CR, Salehi A, Gambhir SS, Chin FT. Further validation to support clinical translation of [(18)F]FTC-146 for imaging sigma-1 receptors. EJNMMI Res. 2015 Dec;5(1):49. doi: 10.1186/s13550-015-0122-2. Epub 2015 Sep 17. PMID: 26384292; PMCID: PMC4573970.
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EJNMMI Res. 2015 Dec;5(1):49. doi: 10.1186/s13550-015-0122-2. Epub 2015 Sep 17.

Further validation to support clinical translation of [(18)F]FTC-146 for imaging sigma-1 receptors.

EJNMMI research

Bin Shen, Michelle L James, Lauren Andrews, Christopher Lau, Stephanie Chen, Mikael Palner, Zheng Miao, Natasha C Arksey, Adam J Shuhendler, Shawn Scatliffe, Kota Kaneshige, Stanley M Parsons, Christopher R McCurdy, Ahmad Salehi, Sanjiv S Gambhir, Frederick T Chin

Affiliations

  1. Molecular Imaging Program at Stanford (MIPS) Department of Radiology Stanford University, Stanford, CA, 94305, USA.
  2. Department of Neurology and Neurological Sciences, Stanford University, Stanford, CA, 94305, USA.
  3. Department of Chemistry and Biochemistry, University of California Santa Barbara, Santa Barbara, CA, 93106, USA.
  4. Department of Medicinal Chemistry and Pharmacology, The University of Mississippi, University, MS, 38677, USA.
  5. Veterans Administration Palo Alto Health Care System, Palo Alto, CA, 94304, USA.
  6. Molecular Imaging Program at Stanford (MIPS) Department of Radiology Stanford University, Stanford, CA, 94305, USA. [email protected].

PMID: 26384292 PMCID: PMC4573970 DOI: 10.1186/s13550-015-0122-2

Abstract

BACKGROUND: This study aims to further evaluate the specificity and selectivity of [(18)F]FTC-146 and obtain additional data to support its clinical translation.

METHODS: The binding of [(19)F]FTC-146 to vesicular acetylcholine transporter (VAChT) was evaluated using [(3)H]vesamicol and PC12(A123.7) cells in an in vitro binding assay. The uptake and kinetics of [(18)F]FTC-146 in S1R-knockout mice (S1R-KO) compared to wild-type (WT) littermates was assessed using dynamic positron emission tomography (PET) imaging. Ex vivo autoradiography and histology were conducted using a separate cohort of S1R-KO/WT mice, and radiation dosimetry was calculated from WT mouse data (extrapolated for human dosing). Toxicity studies in Sprague-Dawley rats were performed with a dose equivalent to 250× the anticipated clinical dose of [(19)F]FTC-146 mass.

RESULTS AND DISCUSSION: VAChT binding assay results verified that [(19)F]FTC-146 displays negligible affinity for VAChT (K i = 450 ± 80 nM) compared to S1R. PET images demonstrated significantly higher tracer uptake in WT vs. S1R-KO brain (4.57 ± 1.07 vs. 1.34 ± 0.4 %ID/g at 20-25 min, n = 4, p < 0.05). In S1R-KO mice, it was shown that rapid brain uptake and clearance 10 min post-injection, which are consistent with previous S1R-blocking studies in mice. Three- to fourfold higher tracer uptake was observed in WT relative to S1R-KO mouse brains by ex vivo autoradiography. S1R staining coincided well with the autoradiographic data in all examined brain regions (r (2) = 0.85-0.95). Biodistribution results further demonstrated high [(18)F]FTC-146 accumulation in WT relative to KO mouse brain and provided quantitative information concerning tracer uptake in S1R-rich organs (e.g., heart, lung, pancreas) for WT mice vs. age-matched S1R-KO mice. The maximum allowed dose per scan in humans as extrapolated from mouse dosimetry was 33.19 mCi (1228.03 MBq). No significant toxicity was observed even at a 250X dose of the maximum carrier mass [(19)F]FTC-146 expected to be injected for human studies.

CONCLUSIONS: Together, these data indicate that [(18)F]FTC-146 binds specifically to S1Rs and is a highly promising radiotracer ready for clinical translation to investigate S1R-related diseases.

Keywords: Dosimetry; Sigma-1 receptor; Sigma-1 receptor knockout mice; Small animal PET; Toxicology; Vesicular acetylcholine transporter; [18F]FTC-146

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