title: Carbon-11 labeled papaverine as a PET tracer for imaging PDE10A: radiosynthesis, in vitro and in vivo evaluation.
abstract: Papaverine, 1-(3,4-dimethoxybenzyl)-6,7-dimethoxyisoquinoline, a specific inhibitor of phosphodiesterase (PDE) 10A with IC(50) values of 36 nM for PDE10A, 1,300 nM for PDE3A and 320 nM for PDE4D, has served as a useful pharmaceutical tool to study the physiological role of PDE10A. Here, we report the radiosynthesis of [(11)C]papaverine and the in vitro and in vivo evaluation of [(11)C]papaverine as a potential positron emission tomography (PET) radiotracer for imaging PDE10A in the central nervous system (CNS). The radiosynthesis of papaverine with (11)C was achieved by O-methylation of the corresponding des-methyl precursor with [(11)C]methyl iodide. [(11)C]papaverine was obtained with approximately 70% radiochemical yield and a specific activity >10 Ci/mumol. In vitro autoradiography studies of rat and monkey brain sections revealed selective binding of [(11)C]papaverine to PDE10A enriched regions: the striatum of rat brain and the caudate and putamen of rhesus monkey brain. The biodistribution of [(11)C]papaverine in rats at 5 min demonstrated an initially higher accumulation in striatum than in other brain regions, however the washout was rapid. MicroPET imaging studies in rhesus macaques similarly displayed initial specific uptake in the striatum with very rapid clearance of [(11)C]papaverine from brain. Our initial evaluation suggests that despite papaverine's utility for in vitro studies and as a pharmaceutical tool, [(11)C]papaverine is not an ideal radioligand for clinical imaging of PDE10A in the CNS. Analogs of papaverine having a higher potency for inhibiting PDE10A and improved pharmacokinetic properties will be necessary for imaging this enzyme with PET.
authors.affiliation: Mallinckrodt Institute of Radiology, Washington University School of Medicine, St. Louis, MO 63110, USA. tuz@mir.wustl.edu
authors.forename: Zhude
authors.initials: Z
authors.lastname: Tu
authors.forename: Jinbin
authors.initials: J
authors.lastname: Xu
authors.forename: Lynne A
authors.initials: LA
authors.lastname: Jones
authors.forename: Shihong
authors.initials: S
authors.lastname: Li
authors.forename: Robert H
authors.initials: RH
authors.lastname: Mach
mesh_terms: D000818:Animals; D001345:Autoradiography; D001692:Biological Transport; D001921:Brain / Q000000981:diagnostic imaging / Q000378:metabolism; D002250:Carbon Radioisotopes / Q000737:chemistry; D008297:Male; D010208:Papaverine / Q000097:blood / Q000378:metabolism* / Q000493:pharmacokinetics; D010727:Phosphoric Diester Hydrolases / Q000378:metabolism*; D049268:Positron-Emission Tomography / Q000379:methods*; D011849:Radioactive Tracers; D011854:Radiochemistry; D051381:Rats
chemical_list: D002250:Carbon Radioisotopes; D011849:Radioactive Tracers; D010208:Papaverine; C512064:PDE10A protein, rat; D010727:Phosphoric Diester Hydrolases
references.citation: Neuropharmacology. 2006 Aug;51(2):386-96
references.pmid: 16780899
references.citation: Xenobiotica. 1975 Jul;5(7):421-9
references.pmid: 1154809
references.citation: Xenobiotica. 1978 May;8(5):297-300
references.pmid: 664752
references.citation: Proc Natl Acad Sci U S A. 1999 Jun 8;96(12):7071-6
references.pmid: 10359840
references.citation: J Biol Chem. 1999 Jun 25;274(26):18438-45
references.pmid: 10373451
references.citation: J Org Chem. 1970 May;35(5):1684-7
references.pmid: 5440344
references.citation: Neuropharmacology. 2006 Aug;51(2):374-85
references.pmid: 16769090
references.citation: Eur J Biochem. 1999 Dec;266(3):1118-27
references.pmid: 10583409
references.citation: J Histochem Cytochem. 2006 Nov;54(11):1205-13
references.pmid: 16864896
references.citation: J Med Chem. 1983 Feb;26(2):174-81
references.pmid: 6298424
references.citation: Brain Res. 2003 Sep 26;985(2):113-26
references.pmid: 12967715
references.citation: Neuroscience. 2006 May 12;139(2):597-607
references.pmid: 16483723
references.citation: Biochem Pharmacol. 1973 Jan 1;22(1):59-66
references.pmid: 4763245
references.citation: J Pharm Sci. 1968 Jun;57(6):940-3
references.pmid: 5677685