¹¹C-MCG: Synthesis, uptake selectivity, and primate PET of a probe for glutamate carboxypeptidase II (NAALADase)

Imaging of glutamate carboxypeptidase II (GCP II), also known as N-acetylated α-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 (K _i = 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.