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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.

Author information

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. chinf@stanford.edu.

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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