Sigma-1 receptors (S1Rs) play an important role in many neurological disorders. Simultaneous positron emission tomography (PET)/magnetic resonance imaging (MRI) with S1R radioligands may provide valuable information for diagnosing and guiding treatment for these diseases. Our previously reported S1R radioligand, [18F]FTC-146, demonstrated high affinity for the S1R (K i = 0.0025 nM) and excellent selectivity for the S1R over the sigma-2 receptor (S2Rs; K i = 364 nM) across several species (from mouse to non-human primate). Herein, we report the clinical-grade radiochemistry filed with exploratory Investigational New Drug (eIND) and first-in-human PET/MRI evaluation of [18F]FTC-146.
[18F]FTC-146 is prepared via a direct [18F] fluoride nucleophilic radiolabeling reaction and formulated in 0.9 % NaCl containing no more than 10 % ethanol through sterile filtration. Quality control (QC) was performed based on USP 823 before doses were released for clinical use. The safety and whole body biodistribution of [18F]FTC-146 were evaluated using a simultaneous PET/MR scanner in two representative healthy human subjects.
[18F]FTC-146 was synthesized with a radiochemical yield of 3.3 ± 0.7 % and specific radioactivity of 8.3 ± 3.3 Ci/μmol (n = 10, decay corrected to EOB). Both radiochemical and chemical purities were >95 %; the prepared doses were stable for 4 h at ambient temperature. All QC test results met specified clinical criteria. The in vivo PET/MRI investigations showed that [18F]FTC-146 rapidly crossed the blood brain barrier and accumulated in S1R-rich regions of the brain. There were also radioactivity distributed in the peripheral organs, i.e., the lungs, spleen, pancreas, and thyroid. Furthermore, insignificant uptake of [18F]FTC-146 was observed in cortical bone and muscle.
A reliable and automated radiosynthesis for providing routine clinical-grade [18F]FTC-146 for human studies was established in a modified GE TRACERlab FXFN. PET/MRI demonstrated the initial tracer biodistribution in humans, and clinical studies investigating different S1R-related diseases are in progress.
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We would like to thank Dr. Erik S. Mittra for servicing as nuclear medicine doctor and Mr. Harsh Gandhi for providing technical support in human study and the MIPS Cyclotron & Radiochemistry Facility and also PET/MRI Metabolic Service Center for their support. This research was financially supported in part by the NCI ICMIC P50 CA114747 (SSG), NIDA R01 DA023205 (CRM), NIGMS P20 GM104932 (CRM), The Ben & Catherine Ivy Foundation (FTC), and General Electric Healthcare Research Support (SB and FTC).
Two healthy human subjects (male, age 31 years; female, age 36 years) were recruited, and written informed consent was obtained via a protocol approved by the Stanford University Institutional Review Board (IRB).
Conflict of Interest
The authors declare that they have no conflicts of interest.
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Shen, B., Park, J.H., Hjørnevik, T. et al. Radiosynthesis and First-In-Human PET/MRI Evaluation with Clinical-Grade [18F]FTC-146. Mol Imaging Biol 19, 779–786 (2017). https://doi.org/10.1007/s11307-017-1064-z
- Automated radiosynthesis
- sigma-1 receptor