Bin Shen1, Jun Hyung Park1, Trine Hjørnevik1,2,3, Peter W Cipriano1, Daehyun Yoon4, Praveen K Gulaka1, Dawn Holly1, Deepak Behera1, Bonnie A Avery5, Sanjiv S Gambhir1, Christopher R McCurdy6, Sandip Biswal7, Frederick T Chin8. 1. 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. 2. Department of Diagnostic Physics, Oslo University Hospital, Oslo, Norway. 3. The Norwegian Medical Cyclotron Centre, Oslo, Norway. 4. Radiological Sciences Laboratory, Department of Radiology, Stanford University, Stanford, CA, 94305, USA. 5. Department of Pharmaceutics, P1-27, University of Florida, Gainesville, FL, 32610, USA. 6. Department of Medicinal Chemistry, College of Pharmacy, University of Florida, Gainesville, FL, 32610, USA. 7. 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. 8. 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.
Abstract
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, [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. PROCEDURES: [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. CONCLUSION: 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.
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, [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. PROCEDURES: [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. CONCLUSION: 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: Francisco Rafael Nieto; Cruz Miguel Cendán; Cristina Sánchez-Fernández; Enrique José Cobos; José Manuel Entrena; Miguel Angel Tejada; Daniel Zamanillo; José Miguel Vela; José Manuel Baeyens Journal: J Pain Date: 2012-10-12 Impact factor: 5.820
Authors: Michelle L James; Bin Shen; Cristina L Zavaleta; Carsten H Nielsen; Christophe Mesangeau; Pradeep K Vuppala; Carmel Chan; Bonnie A Avery; James A Fishback; Rae R Matsumoto; Sanjiv S Gambhir; Christopher R McCurdy; Frederick T Chin Journal: J Med Chem Date: 2012-09-20 Impact factor: 7.446
Authors: Bin Shen; Michelle L James; Lauren Andrews; Christopher Lau; Stephanie Chen; Mikael Palner; Zheng Miao; Natasha C Arksey; Adam J Shuhendler; Shawn Scatliffe; Kota Kaneshige; Stanley M Parsons; Christopher R McCurdy; Ahmad Salehi; Sanjiv S Gambhir; Frederick T Chin Journal: EJNMMI Res Date: 2015-09-17 Impact factor: 3.138
Authors: Sebastiano Intagliata; Hebaalla Agha; Theresa A Kopajtic; Jonathan L Katz; Shyam H Kamble; Abhisheak Sharma; Bonnie A Avery; Christopher R McCurdy Journal: Med Chem Res Date: 2020-07-08 Impact factor: 1.965
Authors: Trine Hjørnevik; Peter W Cipriano; Bin Shen; Jun Hyung Park; Praveen Gulaka; Dawn Holley; Harsh Gandhi; Daehyun Yoon; Erik S Mittra; Greg Zaharchuk; Sanjiv S Gambhir; Christopher R McCurdy; Frederick T Chin; Sandip Biswal Journal: J Nucl Med Date: 2017-06-01 Impact factor: 10.057
Authors: Bin Shen; Deepak Behera; Michelle L James; Samantha T Reyes; Lauren Andrews; Peter W Cipriano; Michael Klukinov; Amanda Brosius Lutz; Timur Mavlyutov; Jarrett Rosenberg; Arnold E Ruoho; Christopher R McCurdy; Sanjiv S Gambhir; David C Yeomans; Sandip Biswal; Frederick T Chin Journal: Theranostics Date: 2017-07-08 Impact factor: 11.556
Authors: François-Xavier Lepelletier; Matthias Vandesquille; Marie-Claude Asselin; Christian Prenant; Andrew C Robinson; David M A Mann; Michael Green; Elizabeth Barnett; Samuel D Banister; Marco Mottinelli; Christophe Mesangeau; Christopher R McCurdy; Inga B Fricke; Andreas H Jacobs; Michael Kassiou; Hervé Boutin Journal: Theranostics Date: 2020-06-29 Impact factor: 11.600
Authors: Lisa L Wilson; Shainnel O Eans; Insitar Ramadan-Siraj; Maria N Modica; Giuseppe Romeo; Sebastiano Intagliata; Jay P McLaughlin Journal: Int J Mol Sci Date: 2022-01-06 Impact factor: 5.923