title: Radiosynthesis and in Vivo Evaluation of Neuropeptide Y5 Receptor (NPY5R) PET Tracers.
abstract: Neuropeptide Y receptor type 5 (NPY5R) is a G-protein coupled receptor (GPCR) that belongs to the subfamily of neuropeptide receptors (NPYR) that mediate the action of endogenous neuropeptide Y (NPY). Animal models and preclinical studies indicate a role for NPY5R in the pathophysiology of depression, anxiety, and obesity and as a target of potential therapeutic drugs. To better understand the pathophysiological involvement of NPY5R, and to measure target occupancy by potential therapeutic drugs, it would be advantageous to measure NPY5R binding in vivo by positron emission tomography (PET). Four potent and selective NPY5R antagonists were radiolabeled via nucleophilic aromatic substitution reactions with [(18)F]fluoride. Of the four radioligands investigated, PET studies in anesthetized baboons showed that [(18)F]LuAE00654 ([(18)F]N-[trans-4-({[4-(2-fluoropyridin-3-yl)thiazol-2-yl]amino}methyl)cyclohexyl]propane-2-sulfonamide) penetrates blood brain barrier (BBB) and a small amount is retained in the brain. Slow metabolism of [(18)F]LuAE00654 was observed in baboon plasma. Blocking studies with a specific NPY5R antagonist demonstrated up to 60% displacement of radioactivity in striatum, the brain region with highest NPY5R binding. Our studies suggest that [(18)F]LuAE00654 can be a potential PET radiotracer for the quantification and occupancy studies of NPY5R drug candidates.
authors.affiliation: Division of Molecular Imaging and Neuropathology, New York State Psychiatric Institute , New York, New York 10032, United States.|Department of Psychiatry and Behavioral Medicine, Stony Brook University , New York, New York 11794, United States.
authors.forename: J S Dileep
authors.initials: JS
authors.lastname: Kumar
authors.affiliation: Chemical & Pharmacokinetic Sciences and Synaptic Transmission, Disease Biological Unit, Lundbeck Research USA , Paramus, New Jersey 07652, United States.
authors.forename: Mary
authors.initials: M
authors.lastname: Walker
authors.affiliation: Chemical & Pharmacokinetic Sciences and Synaptic Transmission, Disease Biological Unit, Lundbeck Research USA , Paramus, New Jersey 07652, United States.
authors.forename: Mathivanan
authors.initials: M
authors.lastname: Packiarajan
authors.affiliation: Chemical & Pharmacokinetic Sciences and Synaptic Transmission, Disease Biological Unit, Lundbeck Research USA , Paramus, New Jersey 07652, United States.
authors.forename: Vrej
authors.initials: V
authors.lastname: Jubian
authors.affiliation: Department of Psychiatry, Columbia University Medical Center , New York, New York 10032, United States.
authors.forename: Jaya
authors.initials: J
authors.lastname: Prabhakaran
authors.affiliation: Chemical & Pharmacokinetic Sciences and Synaptic Transmission, Disease Biological Unit, Lundbeck Research USA , Paramus, New Jersey 07652, United States.
authors.forename: Gamini
authors.initials: G
authors.lastname: Chandrasena
authors.affiliation: Division of Molecular Imaging and Neuropathology, New York State Psychiatric Institute , New York, New York 10032, United States.
authors.forename: Mali
authors.initials: M
authors.lastname: Pratap
authors.affiliation: Department of Psychiatry and Behavioral Medicine, Stony Brook University , New York, New York 11794, United States.
authors.forename: Ramin V
authors.initials: RV
authors.lastname: Parsey
authors.affiliation: Division of Molecular Imaging and Neuropathology, New York State Psychiatric Institute , New York, New York 10032, United States.|Department of Psychiatry, Columbia University Medical Center , New York, New York 10032, United States.
authors.forename: J John
authors.initials: JJ
authors.lastname: Mann
mesh_terms: D000818:Animals; D001596:Benzylamines / Q000138:chemical synthesis* / Q000378:metabolism*; D001921:Brain / Q000000981:diagnostic imaging / Q000378:metabolism*; D004353:Drug Evaluation, Preclinical / Q000379:methods; D007211:Indoles / Q000138:chemical synthesis* / Q000378:metabolism*; D008297:Male; D010215:Papio; D049268:Positron-Emission Tomography / Q000379:methods*; D011485:Protein Binding / Q000502:physiology; D011849:Radioactive Tracers; D019275:Radiopharmaceuticals / Q000138:chemical synthesis* / Q000378:metabolism*; D017476:Receptors, Neuropeptide Y / Q000378:metabolism*; D005466:Fluorocarbons
chemical_list: D001596:Benzylamines; D007211:Indoles; D011849:Radioactive Tracers; D019275:Radiopharmaceuticals; D017476:Receptors, Neuropeptide Y; C568612:(2-(6-fluoro-1H-indol-3-yl)-ethyl)-(3-(2,2,3,3-tetrafluoropropoxy)benzyl)amine; D005466:Fluorocarbons; C100568:neuropeptide Y5 receptor
keywords: Neuropeptide; PET; antagonist; brain; radiotracer