Radiosynthesis and First-In-Human PET/MRI Evaluation with Clinical-Grade [18F]FTC-146

• Published in: Molecular imaging and biology Vol. 19; no. 5; pp. 779 - 786
• Main Authors: Shen, Bin, Park, Jun Hyung, Hjørnevik, Trine, Cipriano, Peter W., Yoon, Daehyun, Gulaka, Praveen K., Holly, Dawn, Behera, Deepak, Avery, Bonnie A., Gambhir, Sanjiv S., McCurdy, Christopher R., Biswal, Sandip, Chin, Frederick T.
• Format: Journal Article
• Language: English
• Published: New York Springer US 01.10.2017; Springer Nature B.V
• Subjects: Adult; Ambient temperature; Azepines - chemical synthesis; Azepines - chemistry; Azepines - pharmacokinetics; Benzothiazoles - chemical synthesis; Benzothiazoles - chemistry; Benzothiazoles - pharmacokinetics; Blood-brain barrier; Brain; Cortical bone; Ethanol; Evaluation; Female; Fluorides; Humans; Imaging; In vivo methods and tests; Lungs; Magnetic Resonance Imaging; Male; Medicine; Medicine & Public Health; Neuroimaging; Neurological diseases; NMR; Nuclear magnetic resonance; Organs; Pancreas; Positron emission; Positron emission tomography; Quality control; Radioactivity; Radiochemistry; Radioisotopes; Radiology; Receptors; Research Article; Selectivity; Sodium chloride; Spleen; Thyroid; Tissue Distribution; Tomography; Automated radiosynthesis; Clinical; sigma-1 receptor; [18F]FTC-146; PET/MRI; Radiopharmaceuticals
• ISSN: 1536-1632; 1860-2002
• DOI: 10.1007/s11307-017-1064-z

Purpose 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, [ 18 F]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 [ 18 F]FTC-146. Procedures [ 18 F]FTC-146 is prepared via a direct [ 18 F] 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 [ 18 F]FTC-146 were evaluated using a simultaneous PET/MR scanner in two representative healthy human subjects. Results [ 18 F]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 [ 18 F]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 [ 18 F]FTC-146 was observed in cortical bone and muscle. Conclusion A reliable and automated radiosynthesis for providing routine clinical-grade [ 18 F]FTC-146 for human studies was established in a modified GE TRACERlab FX FN . PET/MRI demonstrated the initial tracer biodistribution in humans, and clinical studies investigating different S1R-related diseases are in progress.