title: Evaluation of potential PET imaging probes for the orexin 2 receptors.
abstract: A wide range of central nervous system (CNS) disorders, particularly those related to sleep, are associated with the abnormal function of orexin (OX) receptors. Several orexin receptor antagonists have been reported in recent years, but currently there are no imaging tools to probe the density and function of orexin receptors in vivo. To date there are no published data on the pharmacokinetics (PK) and accumulation of some lead orexin receptor antagonists. Evaluation of CNS pharmacokinetics in the pursuit of positron emission tomography (PET) radiotracer development could be used to elucidate the association of orexin receptors with diseases and to facilitate the drug discovery and development. To this end, we designed and evaluated carbon-11 labeled compounds based on diazepane orexin receptor antagonists previously described. One of the synthesized compounds, [(11)C]CW4, showed high brain uptake in rats and further evaluated in non-human primate (NHP) using PET-MR imaging. PET scans performed in a baboon showed appropriate early brain uptake for consideration as a radiotracer. However, [(11)C]CW4 exhibited fast kinetics and high nonspecific binding, as determined after co-administration of [(11)C]CW4 and unlabeled CW4. These properties indicate that [(11)C]CW4 has excellent brain penetrance and could be used as a lead compound for developing new CNS-penetrant PET imaging probes of orexin receptors.
authors: Athinoula A. Martinos Center for Biomedical Imaging, Department of Radiology, Massachusetts General Hospital, Harvard Medical School, Charlestown, MA, 02129, United States.
authors: Changning
authors: C
authors: Wang
authors: Colin M
authors: CM
authors: Wilson
authors: Christian K
authors: CK
authors: Moseley
authors: Stephen M
authors: SM
authors: Carlin
authors: Shirley
authors: S
authors: Hsu
authors: Grae
authors: G
authors: Arabasz
authors: Frederick A
authors: FA
authors: Schroeder
authors: Christin Y
authors: CY
authors: Sander
authors: Jacob M
authors: JM
authors: Hooker
mesh_terms: D000818:Animals; D001381:Azepines / Q000138:chemical synthesis / Q000737:chemistry / Q000378:metabolism; D001812:Blood-Brain Barrier / Q000000981:diagnostic imaging / Q000378:metabolism; D015195:Drug Design; D008297:Male; D064446:Orexin Receptors / Q000378:metabolism*; D010215:Papio; D049268:Positron-Emission Tomography / Q000379:methods*; D011854:Radiochemistry; D051381:Rats; D014057:Tomography, X-Ray Computed
chemical_list: D001381:Azepines; D064446:Orexin Receptors
keywords: Carbon-11; Hypocretin; Imaging; Orexin; PET radiotracers
references: Neuropsychopharmacology. 2012 Apr;37(5):1224-33
references: 22237311
references: J Psychopharmacol. 2012 Aug;26(8):1058-70
references: 21730017
references: Bioorg Med Chem Lett. 2012 Mar 15;22(6):2172-4
references: 22364813
references: Br J Pharmacol. 2009 Apr;156(8):1326-41
references: 19751316
references: Nat Med. 2007 Feb;13(2):150-5
references: 17259994
references: J Neurogenet. 2011 Mar;25(1-2):52-61
references: 21473737
references: Sleep. 2012 Aug 01;35(8):1097-104
references: 22851805
references: ACS Chem Neurosci. 2012 Jan 18;3(1):50-68
references: 22267984
references: ChemMedChem. 2009 Jul;4(7):1069-74
references: 19418500
references: Neurology. 2012 Dec 4;79(23):2265-74
references: 23197752
references: Proc Natl Acad Sci U S A. 1998 Jan 6;95(1):322-7
references: 9419374
references: Bioorg Med Chem Lett. 2003 Dec 15;13(24):4497-9
references: 14643355
references: Expert Opin Investig Drugs. 2007 Nov;16(11):1785-97
references: 17970638
references: J Comp Neurol. 2001 Jun 18;435(1):6-25
references: 11370008
references: Annu Rev Psychol. 2004;55:125-48
references: 14744212
references: Synapse. 2011 Aug;65(8):778-87
references: 21218455
references: Br J Pharmacol. 2008 Mar;153 Suppl 2:S1-209
references: 18347570