<SUP>11</SUP>C-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.

PET Imaging in Prostate Cancer: Focus on Prostate-Specific Membrane Antigen

“…2) [118, 119]. This was prepared by methylation of the cysteine-glutamate urea precursor 7 with 11 C-methyl iodide in dimethylformamide previously saturated with anhydrous ammonia.…”

PSMA-Targeted Theranostic Nanoplex for Prostate Cancer Therapy

“…After 2 h of incubation, the uptake of 5 nM nanoplex 1 in PC3-PIP was high whereas the uptake of 5 nM of nanoplex 2 in PC3-PIP was much lower. When excess PMPA (2-phosphonomethylpentanedioic acid) 35,36 was added to block PSMA, the uptake of nanoplex 1 in PC3-PIP cells decreased to levels similar to the uptake of nanoplex 2 . When nanoplex 1 or 2 was added to PC3-Flu cells that have low PSMA expression, the uptake was low.…”

Molecular-Genetic Imaging of Cancer

“…For example, we recently tested the prostate-specific membrane antigen (PSMA) as an imaging reporter and showed it performed as well or better than HSV1-tk or hNIS for imaging of animal models of human cancer (Castanares et al, 2014). PSMA would be a good candidate for a theranostic reporter as many imaging and therapeutic probes have already been developed for this human protein (Banerjee et al, 2008; Chen et al, 2009, 2008; Foss et al, 2005; Hillier et al, 2009; Mease et al, 2008; Pomper et al, 2002; Shallal et al, 2014), including several radiolabeled molecules that are in clinical trials (Barrett et al, 2013; Cho et al, 2012; Hillier et al, 2011). …”