title: Synthesis of a 11C-labeled NK1 receptor ligand for PET studies.
abstract: Changes in substance P (SP) receptor concentration have been implicated in neuropsychiatric disorders, Parkinson's disease, arthritis, inflammatory bowel disease and asthma. Since, SP and peptide analogs are rapidly metabolized and do not penetrate into the CNS, they are not useful for PET. Recently, a non-peptide SP antagonist, (+)-(2S,3S)-3-(2-methoxybenzylamino)-2-phenylpiperidine (CP-99,994) was developed. As a prelude to PET studies, this compound was radiolabeled with 11C and biodistribution was determined in hamsters. CP-99,994 was radiolabeled by methylation of tert-Boc, desmethyl CP-99,994 with 11CH3I followed by deprotection and HPLC purification. The time required for the synthesis was 40 min from the end of bombardment. Radiochemical purity of the final product was > 95% and specific activity was routinely > 1000 mCi/mumol [EOS]. The biodistribution of 11C-CP-99,994 was determined in groups of six Syrian hamsters at 5 and 30 min after injection. The results of these studies demonstrated that significant concentrations (%ID/g +/- SEM) of CP-99,994 accumulate in most tissues of the hamster. The highest levels of drug were detected in the lung: 21.04 +/- 1.26 (5 min) and 13.49 +/- 1.71 (30 min). Brain accumulation was: 1.44 +/- 0.06 (5 min), 1.32 +/- 0.05 (30 min). These results indicate that 11C-CP-99,994 can be prepared in high purity and specific activity. This new radiopharmaceutical may be useful for studying both central and peripheral SP receptors by PET.
authors.affiliation: Department of Radiology, Massachusetts General Hospital, Boston 02114, USA.
authors.forename: E
authors.initials: E
authors.lastname: Livni
authors.forename: J W
authors.initials: JW
authors.lastname: Babich
authors.forename: M C
authors.initials: MC
authors.lastname: Desai
authors.forename: D M
authors.initials: DM
authors.lastname: Godek
authors.forename: R A
authors.initials: RA
authors.lastname: Wilkinson
authors.forename: R H
authors.initials: RH
authors.lastname: Rubin
authors.forename: A J
authors.initials: AJ
authors.lastname: Fischman
mesh_terms: D000818:Animals; D002250:Carbon Radioisotopes; D006224:Cricetinae; D008297:Male; D008647:Mesocricetus; D015288:Neurokinin A / Q000037:antagonists & inhibitors*; D010880:Piperidines / Q000138:chemical synthesis* / Q000493:pharmacokinetics; D018040:Receptors, Neurokinin-1 / Q000032:analysis*; D014018:Tissue Distribution; D014055:Tomography, Emission-Computed
chemical_list: D002250:Carbon Radioisotopes; D010880:Piperidines; D018040:Receptors, Neurokinin-1; C080755:3-(2-methoxybenzylamino)-2-phenylpiperidine; D015288:Neurokinin A