Interactions between human glutamate carboxypeptidase II and urea-based inhibitors: structural characterization.

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.

N-[N-[(S)-1,3-Dicarboxypropyl]carbamoyl]-4-[18F]fluorobenzyl-L-cysteine, [18F]DCFBC: a new imaging probe for prostate cancer.

Purpose: Previously, we showed successful imaging of xenografts that express the prostate-specific membrane antigen (PSMA) using small-animal positron emission tomography (PET) and the radiolabeled PSMA inhibitor N-[N-[(S)-1,3-dicarboxypropyl]carbamoyl]-S-[11C]methyl-l-cysteine. Herein, we extend that work by preparing and testing a PSMA inhibitor of the same class labeled with fluorine-18.

Experimental Design: N-[N-[(S)-1,3-Dicarboxypropyl]carbamoyl]-4-[18F]fluorobenzyl-l-cysteine ([18F]DCFBC) was prepared by reacting 4-[18F]fluorobenzyl bromide with the precursor (S)-2-[3-[(R)-1-carboxy-2-mercaptoethyl]ureido]-pentanedioic acid in ammonia-saturated methanol at 60 degrees C for 10 min followed by purification using C-18 reverse-phase semipreparative high-performance liquid chromatography.

Catalytic, asymmetric alpha-chlorination of acid halides.

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.