title: Evaluation of [4-O-methyl-(11)C]KW-6002 as a potential PET ligand for mapping central adenosine A(2A) receptors in rats.
abstract: KW-6002, a xanthine-based adenosine A(2A) antagonist, was labelled with the positron emitter carbon-11 by O-methylation of its precursor, KF23325, using [(11)C]iodomethane and was evaluated in rats as a putative in vivo radioligand for positron emission tomography (PET). Following intravenous injection of [(11)C]KW-6002, radioactivity was measured in blood, plasma, peripheral tissues, and in discrete brain tissues over a 2-h time period commensurate with PET scanning. In brain, [(11)C]KW-6002 showed highest retention in striata, with evidence of saturable binding, and lowest retention in frontal cortex (a tissue low in adenosine A(2A) receptors). PET scanning with [(11)C]KW-6002 demonstrated a specific signal in the striata which could be described using compartmental modelling. Specific binding was, however, also detected in extrastriatal regions, including brain areas reported to have low adenosine A(2A) receptor density. Blocking studies with the A(1) selective antagonist KF15372 and the non xanthine-type A(2A) antagonist ZM 241385 failed to elucidate the nature of this binding. Thus, although [(11)C]KW-6002 shows some potential for development as a PET ligand for quantifying striatal adenosine A(2A) receptor function, its in vivo selectivity requires further investigation.
authors.affiliation: Imaging Research Solutions Ltd and PET Methodology Group, MRC Clinical Sciences Centre, Hammersmith Hospital, London W12 0NN, UK. ella.hirani@ic.ac.uk
authors.forename: E
authors.initials: E
authors.lastname: Hirani
authors.forename: J
authors.initials: J
authors.lastname: Gillies
authors.forename: A
authors.initials: A
authors.lastname: Karasawa
authors.forename: J
authors.initials: J
authors.lastname: Shimada
authors.forename: H
authors.initials: H
authors.lastname: Kase
authors.forename: J
authors.initials: J
authors.lastname: Opacka-Juffry
authors.forename: S
authors.initials: S
authors.lastname: Osman
authors.forename: S K
authors.initials: SK
authors.lastname: Luthra
authors.forename: S P
authors.initials: SP
authors.lastname: Hume
authors.forename: D J
authors.initials: DJ
authors.lastname: Brooks
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry; D001921:Brain / Q000000981:diagnostic imaging*; D001923:Brain Chemistry; D002250:Carbon Radioisotopes; D008024:Ligands; D008297:Male; D011687:Purines / Q000737:chemistry; D019275:Radiopharmaceuticals / Q000737:chemistry / Q000493:pharmacokinetics; D051381:Rats; D017207:Rats, Sprague-Dawley; D043705:Receptor, Adenosine A2A; D018047:Receptors, Purinergic P1 / Q000032:analysis / Q000378:metabolism*; D014055:Tomography, Emission-Computed / Q000379:methods*
chemical_list: D000970:Antineoplastic Agents; D002250:Carbon Radioisotopes; D008024:Ligands; D011687:Purines; D019275:Radiopharmaceuticals; D043705:Receptor, Adenosine A2A; D018047:Receptors, Purinergic P1; C111599:istradefylline