title: Radiosynthesis, ex vivo and in vivo evaluation of [11C]preclamol as a partial dopamine D2 agonist radioligand for positron emission tomography.
abstract: Dopamine D2 partial agonists have been successfully used as schizophrenia therapeutics. Radiolabeled D2 partial agonists may have application in elucidating dopaminergic transmission. It was the goal of this work to radiolabel (S)-(-)propyl-3-(3-hydroxyphenyl)piperidine (preclamol; (-)3-PPP), a partial dopamine D2 agonist with carbon-11 (half-life=20.4 min) and to evaluate this novel radiopharmaceutical for dopaminergic imaging in rodent models. [11C]Preclamol was synthesized by acylation of (S)-3-(3-hydroxyphenyl)piperidine hydrochloride with [11C]propionyl chloride, followed by LiAlH4 reduction, and HPLC purification. Male Sprague-Dawley rats were injected in the tail vein with a saline solution of [11C]preclamol (1.1 mug/kg) and sacrificed at 5, 15, 30 and 60 min postinjection. Brain regions were excised, weighed, and measured for radioactivity. In vivo binding kinetics of [11C]preclamol were determined with beta-sensitive microprobes implanted into the striatum and cerebellum of an anesthetized rat. A full production of [11C]preclamol resulted in 34 mCi ready for injection (corresponding to 4% uncorrected radiochemical yield, based on starting [11C]CO2) with specific activity of 535 mCi/micromol. The total synthesis time was 45 min and resulted in chemically and radiochemically pure [11C]preclamol (>99%; n=3). High levels of radioactivity were observed in rat brain indicating good blood-brain barrier penetration of [11C]preclamol, with 0.5 to 0.7% injected dose per gram of wet tissue present in all brain regions at 5 minutes postinjection. Unfortunately, [11C]preclamol displayed minimal preferential uptake in dopaminergic brain regions. A low striatal specific binding (SB) ratio of 0.32 was determined ex vivo at 60 min postinjection and was in close agreement with the microprobe study over 60 min (peaked at 27 min postinjection; SB ratio=0.6). The binding potential value was only 0.34 over a 1 hour time course, suggesting that [11C]preclamol is not suitable for cerebral PET studies.
authors.affiliation: PET Centre, Centre for Addiction and Mental Health, Toronto, Ontario, Canada, M5T-1R8. neil.vasdev@camhpet.ca
authors.forename: Neil
authors.initials: N
authors.lastname: Vasdev
authors.forename: Sridhar
authors.initials: S
authors.lastname: Natesan
authors.forename: Laurent
authors.initials: L
authors.lastname: Galineau
authors.forename: Armando
authors.initials: A
authors.lastname: Garcia
authors.forename: Winston T
authors.initials: WT
authors.lastname: Stableford
authors.forename: Patrick
authors.initials: P
authors.lastname: McCormick
authors.forename: Philip
authors.initials: P
authors.lastname: Seeman
authors.forename: Sylvain
authors.initials: S
authors.lastname: Houle
authors.forename: Alan A
authors.initials: AA
authors.lastname: Wilson
mesh_terms: D000818:Animals; D001812:Blood-Brain Barrier; D001921:Brain / Q000000981:diagnostic imaging*; D001923:Brain Chemistry; D055598:Chemical Phenomena; D002627:Chemistry, Physical; D018491:Dopamine Agonists / Q000494:pharmacology*; D007202:Indicators and Reagents; D007275:Injections, Intravenous; D007553:Isotope Labeling; D008297:Male; D010880:Piperidines / Q000008:administration & dosage / Q000138:chemical synthesis*; D049268:Positron-Emission Tomography / Q000379:methods*; D019275:Radiopharmaceuticals / Q000008:administration & dosage / Q000138:chemical synthesis*; D051381:Rats; D017207:Rats, Sprague-Dawley; D017448:Receptors, Dopamine D2 / Q000819:agonists*
chemical_list: D018491:Dopamine Agonists; D007202:Indicators and Reagents; D010880:Piperidines; D019275:Radiopharmaceuticals; D017448:Receptors, Dopamine D2; C026539:preclamol