title: 11C-MCG: synthesis, uptake selectivity, and primate PET of a probe for glutamate carboxypeptidase II (NAALADase).
abstract: Imaging of glutamate carboxypeptidase II (GCP II), also known as N-acetylated alpha-linked L-amino dipeptidase (NAALADase), may enable study of glutamatergic transmission, prostate cancer, and tumor neovasculature in vivo. Our goal was to develop a probe for GCP II for use with positron emission tomography (PET). Radiosynthesis of 11C-MeCys-C(O)-Glu or 11C-(S)-2-[3-((R)-1-carboxy-2-methylsulfanyl-ethyl)-ureido]-pentanedioic acid (11C-MCG), an asymmetric urea and potent (Ki = 1.9 nM) inhibitor of GCP II, was performed by C-11 methylation of the free thiol. Biodistribution of 11C-MCG was assayed in mice, and quantitative PET was performed in a baboon. 11C-MCG was obtained in 16% radiochemical yield at the end of synthesis with specific radioactivities over 167 GBq/mmol (4000 Ci/mmol) within 30 min after the end of bombardment. At 30 min postinjection, 11C-MCG showed 33.0 +/- 5.1%, 0.4 +/- 0.1%, and 1.1 +/- 0.2% ID/g in mouse kidney (target tissue), muscle, and blood, respectively. Little radioactivity gained access to the brain. Blockade with unlabeled MCG or 2-(phosphonomethyl)pentanedioic acid (PMPA), another potent inhibitor of GCP II, provided sevenfold and threefold reductions, respectively, in binding to target tissue. For PET, distribution volumes (DVs) were 1.38 then 0.87 pre- and postblocker (PMPA). Little metabolism of 11C-MCG occurred in the mouse or baboon. These results suggest that 11C-MCG may be useful for imaging GCP II in the periphery.
authors.affiliation: Division of Neuroradiology, Johns Hopkins University School of Medicine, 600 N. Wolfe St., Baltimore, MD 21287-2182, USA. mpomper@jhmi.edu
authors.forename: Martin G
authors.initials: MG
authors.lastname: Pomper
authors.forename: John L
authors.initials: JL
authors.lastname: Musachio
authors.forename: Jiazhong
authors.initials: J
authors.lastname: Zhang
authors.forename: Ursula
authors.initials: U
authors.lastname: Scheffel
authors.forename: Yun
authors.initials: Y
authors.lastname: Zhou
authors.forename: John
authors.initials: J
authors.lastname: Hilton
authors.forename: Atul
authors.initials: A
authors.lastname: Maini
authors.forename: Robert F
authors.initials: RF
authors.lastname: Dannals
authors.forename: Dean F
authors.initials: DF
authors.lastname: Wong
authors.forename: Alan P
authors.initials: AP
authors.lastname: Kozikowski
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D002250:Carbon Radioisotopes / Q000493:pharmacokinetics*; D002268:Carboxypeptidases / Q000378:metabolism*; D043425:Glutamate Carboxypeptidase II; D005977:Glutarates / Q000493:pharmacokinetics*; D008297:Male; D008745:Methylation; D051379:Mice; D023421:Models, Animal; D010215:Papio; D014018:Tissue Distribution; D014055:Tomography, Emission-Computed / Q000379:methods*
chemical_list: C478125:(S)-2-(3-((R)-1-carboxy-2-methylsulfanyl-ethyl)-ureido)pentanedioic acid; D002250:Carbon Radioisotopes; D005977:Glutarates; D002268:Carboxypeptidases; D043425:Glutamate Carboxypeptidase II