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

Autor: Shen B; 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., Park JH; 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., Hjørnevik T; 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., Cipriano PW; 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., Yoon D; Radiological Sciences Laboratory, Department of Radiology, Stanford University, Stanford, CA, 94305, USA., Gulaka PK; 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., Holly D; 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., Behera D; 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., Avery BA; Department of Pharmaceutics, P1-27, University of Florida, Gainesville, FL, 32610, USA., Gambhir SS; 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., McCurdy CR; Department of Medicinal Chemistry, College of Pharmacy, University of Florida, Gainesville, FL, 32610, USA., Biswal S; 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., Chin FT; 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.
Jazyk: angličtina
Zdroj: Molecular imaging and biology [Mol Imaging Biol] 2017 Oct; Vol. 19 (5), pp. 779-786.
DOI: 10.1007/s11307-017-1064-z
Abstrakt: 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.
Databáze: MEDLINE
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