title: Radiosynthesis and First-In-Human PET/MRI Evaluation with Clinical-Grade [18F]FTC-146.
abstract: OBJECTIVE
  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 (Ki= 0.0025 nM) and excellent selectivity for the S1R over the sigma-2 receptor (S2Rs; Ki= 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.
  
  
  METHODS
  [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.
  
  
  RESULTS
  [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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Molecular Imaging Program at Stanford (MIPS), Departments of Radiology and Bioengineering, Bio-X Program, Stanford University School of Medicine, 1201 Welch Road, PS049, Stanford, CA, 94305-5484, USA.
authors.forename: Bin
authors.initials: B
authors.lastname: Shen
authors.affiliation: Molecular Imaging Program at Stanford (MIPS), Departments of Radiology and Bioengineering, Bio-X Program, Stanford University School of Medicine, 1201 Welch Road, PS049, Stanford, CA, 94305-5484, USA.
authors.forename: Jun Hyung
authors.initials: JH
authors.lastname: Park
authors.affiliation: Molecular Imaging Program at Stanford (MIPS), Departments of Radiology and Bioengineering, Bio-X Program, Stanford University School of Medicine, 1201 Welch Road, PS049, Stanford, CA, 94305-5484, USA.|Department of Diagnostic Physics, Oslo University Hospital, Oslo, Norway.|The Norwegian Medical Cyclotron Centre, Oslo, Norway.
authors.forename: Trine
authors.initials: T
authors.lastname: Hjørnevik
authors.affiliation: Molecular Imaging Program at Stanford (MIPS), Departments of Radiology and Bioengineering, Bio-X Program, Stanford University School of Medicine, 1201 Welch Road, PS049, Stanford, CA, 94305-5484, USA.
authors.forename: Peter W
authors.initials: PW
authors.lastname: Cipriano
authors.affiliation: Radiological Sciences Laboratory, Department of Radiology, Stanford University, Stanford, CA, 94305, USA.
authors.forename: Daehyun
authors.initials: D
authors.lastname: Yoon
authors.affiliation: Molecular Imaging Program at Stanford (MIPS), Departments of Radiology and Bioengineering, Bio-X Program, Stanford University School of Medicine, 1201 Welch Road, PS049, Stanford, CA, 94305-5484, USA.
authors.forename: Praveen K
authors.initials: PK
authors.lastname: Gulaka
authors.affiliation: Molecular Imaging Program at Stanford (MIPS), Departments of Radiology and Bioengineering, Bio-X Program, Stanford University School of Medicine, 1201 Welch Road, PS049, Stanford, CA, 94305-5484, USA.
authors.forename: Dawn
authors.initials: D
authors.lastname: Holly
authors.affiliation: Molecular Imaging Program at Stanford (MIPS), Departments of Radiology and Bioengineering, Bio-X Program, Stanford University School of Medicine, 1201 Welch Road, PS049, Stanford, CA, 94305-5484, USA.
authors.forename: Deepak
authors.initials: D
authors.lastname: Behera
authors.affiliation: Department of Pharmaceutics, P1-27, University of Florida, Gainesville, FL, 32610, USA.
authors.forename: Bonnie A
authors.initials: BA
authors.lastname: Avery
authors.affiliation: Molecular Imaging Program at Stanford (MIPS), Departments of Radiology and Bioengineering, Bio-X Program, Stanford University School of Medicine, 1201 Welch Road, PS049, Stanford, CA, 94305-5484, USA.
authors.forename: Sanjiv S
authors.initials: SS
authors.lastname: Gambhir
authors.affiliation: Department of Medicinal Chemistry, College of Pharmacy, University of Florida, Gainesville, FL, 32610, USA.
authors.forename: Christopher R
authors.initials: CR
authors.lastname: McCurdy
authors.affiliation: Department of Radiology and Molecular Imaging Program at Stanford (MIPS), Stanford University School of Medicine, 300 Pasteur Drive S-068B, Stanford, CA, 94305, USA. biswal@stanford.edu.
authors.forename: Sandip
authors.initials: S
authors.lastname: Biswal
authors.affiliation: Molecular Imaging Program at Stanford (MIPS), Departments of Radiology and Bioengineering, Bio-X Program, Stanford University School of Medicine, 1201 Welch Road, PS049, Stanford, CA, 94305-5484, USA. chinf@stanford.edu.
authors.forename: Frederick T
authors.initials: FT
authors.lastname: Chin
mesh_terms: D000328:Adult; D001381:Azepines / Q000138:chemical synthesis* / Q000737:chemistry* / Q000493:pharmacokinetics; D052160:Benzothiazoles / Q000138:chemical synthesis* / Q000737:chemistry* / Q000493:pharmacokinetics; D005260:Female; D006801:Humans; D008279:Magnetic Resonance Imaging; D008297:Male; D049268:Positron-Emission Tomography; D014018:Tissue Distribution
chemical_list: C577112:6-(3-fluoropropyl)-3-(2-(azepan-1-yl)ethyl)benzo(d)thiazol-2(3H)-one; D001381:Azepines; D052160:Benzothiazoles
keywords: Automated radiosynthesis; Clinical; PET/MRI; Radiopharmaceuticals; [18F]FTC-146; sigma-1 receptor