N -[18 F]-FluoropropylJDTic for κ-Opioid Receptor PET Imaging: Radiosynthesis, Pre-clinical Evaluation, and Metabolic Investigation in Comparison with Parent JDTic

• Published in: Nuclear medicine and biology 2017-01, Vol.44, p.50-61
• Main Authors: Schmitt, Sébastien, Delamare, Jérôme, Tirel, Olivier, Fillesoye, Fabien, Dhilly, Martine, Perrio, Cécile
• Format: Article
• Language: English
• Subjects: Animals; Chemical Sciences; Chemistry Techniques, Synthetic; Fluorine Radioisotopes; Fluorine-18; Humans; JDTic; kappa Opioid receptor; Life Sciences; Ligands; Male; Metabolism; Mice; Microsomes, Liver - metabolism; Models, Molecular; Molecular Conformation; N-fluoroalkylation; PET imaging; Piperidines - chemical synthesis; Piperidines - chemistry; Piperidines - metabolism; Piperidines - pharmacokinetics; Positron-Emission Tomography - methods; Radiochemistry; Radiology; Receptors, Opioid, kappa - metabolism; Tetrahydroisoquinolines - chemical synthesis; Tetrahydroisoquinolines - chemistry; Tetrahydroisoquinolines - metabolism; Tetrahydroisoquinolines - pharmacokinetics; Tissue Distribution
• ISSN: 0969-8051; 1872-9614
• DOI: 10.1016/j.nucmedbio.2016.09.005

Abstract Introduction To image kappa opioid receptor (KOR) for preclinical studies, N -fluoropropylJDTic 9 derived from the best-established KOR antagonist JDTic, was labeled with fluorine-18. Methods Radiosynthesis of [18 F] 9 was achieved according to an automated two-step procedure from [18 F]-fluoride. Peripheral and cerebral distributions were determined by ex vivo experiments and by PET imaging in mouse. Radiometabolism studies were performed both in vivo in mice and in vitro in mouse and human liver microsomes. Identification of the major metabolic fragmentations was carried out by UPLC-MS analysis of enzymatic cleavage of non-radioactive ligand 9 . Microsomal metabolic degradation of parent JDTic was also achieved for comparison. Results The radiotracer [18 F] 9 was produced after 140 ± 5 min total synthesis time (2.2 ± 0.4% not decay corrected radiochemical yield) with a specific activity of 41–89 GBq/μmol (1.1–2.4 Ci/μmol). Peripheral and regional brain distributions of [18 F] 9 were consistent with known KOR locations but no significant specific binding in brain was shown. [18 F] 9 presented a typical hepatobiliary and renal elimination, and was rapidly metabolized. The in vivo and in vitro radiometabolic profiles of [18 F] 9 were similar. Piperidine 12 was identified as the major metabolic fragment of the non-radioactive ligand 9 . JDTic 7 was found to be much more stable than 9. Conclusion Although the newly proposed radioligand [18 F] 9 was concluded to be not suitable for KOR PET imaging due to the formation of brain penetrating radiometabolites, our findings highlight the metabolic stability of JDTic and may help in the design of novel JDTic derivatives for in vivo applications.