Urea-based, low molecular weight ligands of glutamate carboxypeptidase II (GCPII) have demonstrated efficacy in various models of neurological disorders and can serve as imaging agents for prostate cancer. To enhance further development of such compounds, we determined X-ray structures of four complexes between human GCPII and urea-based inhibitors at high resolution. All ligands demonstrate an invariant glutarate moiety within the S1′ pocket of the enzyme. The ureido linkage between P1 and P1′ inhibitor sites interacts with the active-site Zn12+ ion and the side chains of Tyr552 and His553. Interactions within the S1 pocket are defined primarily by a network of hydrogen bonds between the P1 carboxylate group of the inhibitors and the side chains of Arg534, Arg536, and Asn519. Importantly, we have identified a hydrophobic pocket accessory to the S1 site that can be exploited for structure-based design of novel GCPII inhibitors with increased lipophilicity.

Purpose: Previously, we showed successful imaging of xenografts that express the prostatespecific membrane antigen (PSMA) using small-animal positron emission tomography (PET) and the radiolabeled PSMA inhibitor]methyl-L-cysteine. Herein, we extend that work by preparing and testing a PSMA inhibitor of the same class labeled with fluorine-18. High radiopharmaceutical uptake was also seen in kidneys and bladder; however, washout of radioactivity from these organs was faster than from the PIP tumors. The maximum PIP tumor uptake was 8.16 F 2.55% injected dose per gram, achieved at 60 min after injection, which decreased to 4.69 F 0.89 at 120 min. The PIP tumor to muscle ratio was 20 at 120 min after injection. Based on the mouse biodistribution, the dose-limiting organ is the kidneys (human estimated absorbed dose: 0.05 mGy/MBq; 0.2 rad/mCi). Conclusion: [

We present a full account of a tandem catalytic, asymmetric chlorination/esterification process that produces highly optically enriched alpha-chloroesters from inexpensive, commercially available acid halides using cinchona alkaloid derivatives as catalysts and polychlorinated quinones as halogenating agents. We have performed kinetics and control experiments to investigate the reaction mechanism and establish conditions under which the reactions can be best performed. We have developed NaH and NaHCO3 shuttle base systems as the easiest and most cost-effective ways of conducting the reactions, rendering the methodology economically competitive with known chiral halogenation procedures. We have also demonstrated the utility of our reactions by converting the products to synthetically useful derivatives.