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 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 ( 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.

Radiolabeled Small-Molecule Ligands for Prostate-Specific Membrane Antigen: In vivo Imaging in Experimental Models of Prostate Cancer

“…All chemicals and solvents were of American Chemical Society or high-performance liquid chromatography (HPLC) purity and were used as received. (14).…”

Dysregulation of glutamate carboxypeptidase II in psychiatric disease

“…GCPII, also known as the prostatespecific membrane antigen (PSMA), is a peptidase expressed within prostate ≫ brain > kidney, liver, small intestine, spleen, trachea and spinal cord (Lambert and Mitchell, 2007). It is a known marker for prostate cancer, in which it is upregulated, and is a viable in vivo imaging target for this disease in both experimental animals and man (Pomper et al, 2002), , .…”

PSMA-Based Radioligand Therapy for Metastatic Castration-Resistant Prostate Cancer: The Bad Berka Experience Since 2013

“…68 Ga-PSMA PET/CT is pivotal in selecting mCRPC patients with strong PSMA expression, identifying responders, and personalizing PRLT regimens (12). There is ample evidence of the utility of PET/CT in assessing response, such as with 18 F-FDG after radioimmunotherapy of non-Hodgkin lymphoma and with 68 Ga-somatostatin analogs after peptide receptor radionuclide therapy of neuroendocrine tumors (13,14). Similarly, in PRLT, 68 Ga-PSMA PET/CT could play an important role in determining prognosis, monitoring therapy, and following up over the long term.…”

“…The research group at Johns Hopkins, in 2002, was the first to implement imaging with a small molecule that targets PSMA (18). The related compounds 123 I-MIP-1072 and 123 I-MIP-1095, also bearing a urea-based scaffold, have been used to detect metastatic prostate cancer with SPECT (19).…”