Design of Remarkably Simple, Yet Potent Urea-Based Inhibitors of Glutamate Carboxypeptidase II (NAALADase)

Abstract

Introduction.The amino acid glutamate is present in high concentrations in the mammalian brain, and it acts as the major excitatory neurotransmitter in the CNS. Through its actions on both ionotropic and metabotropic receptors, glutamate plays an important role in a variety of physiological functions including learning, memory, and developmental plasticity. Excessive activation of glutamate receptors or disturbances in the cellular mechanisms that protect against the adverse consequences of physiological glutamate receptor activation have been implicated in the pathogenesis of a host of neurological disorders. Although several drugs designed to attenuate the pathological consequences of excessive glutamate activation have been shown to reduce injury in experimental models of cerebral ischemia, so far none of these compounds has proven to be effective in the clinical treatment of stroke. 1 N-Acetyl-L-aspartyl-L-glutamate (NAAG) is a peptide neurotransmitter that is widely distributed in the mammalian nervous system. 2 NAAG is both an agonist at metabotropic glutamate receptors (mGluR3) 3 and a mixed agonist/antagonist at the N-methyl-D-aspartate (NMDA) receptor. 4 NAAG is hydrolyzed by the neuropeptidase glutamate carboxypeptidase II (GCPII; also known as N-acetylated R-linked acidic dipeptidase, NAALADase, or NAAG peptidase) to liberate N-acetylaspartate and glutamate both in vitro and in vivo. 5 The role of this metalloprotease GCPII is thus thought to be twofold: (1) to terminate the neurotransmitter activity of NAAG and (2) to liberate glutamate which is then able to act at the various glutamate receptor subtypes. Alterations in the levels of GCPII and NAAG have been observed in disorders that are linked to abnormalities in glutamatergic neurotransmission. 6 As a consequence of these findings, it has been hypothesized that the inhibition of GCPII might provide an effective strategy for achieving neuroprotection in cases of cerebral ischemia by increasing the levels of

N-[N-[(S)-1,3-Dicarboxypropyl]Carbamoyl]-4-[18F]Fluorobenzyl-l-Cysteine, [18F]DCFBC: A New Imaging Probe for Prostate Cancer

“…The synthesis of 6 is a modification of the route previously described by Kozikowski et al (13) where the benzyl protecting groups are now replaced by the acid labile p-methoxybenzyl groups. In particular, the carboxyl group of commercial N a -Fmoc-S-tert-butyl-L- (1) is protected as a p-methoxybenzyl ester to give 2.…”

Glu-Ureido–Based Inhibitors of Prostate-Specific Membrane Antigen: Lessons Learned During the Development of a Novel Class of Low-Molecular-Weight Theranostic Radiotracers

“…However, all such substitutions reported to date have failed to provide viable leads and instead have resulted in compounds with substantially lower PSMA affinities (9,(44)(45)(46). Likewise, a search for a new "ultimate" zinc-binding group has not been successful; consequently, ureido-based PSMA inhibitor scaffolds are currently the most prevalent theranostic PSMA-targeting vectors used, followed only by transition-state mimetics, such as phosphoramidates (47).…”

“…PSMA-11 belongs to the class of low-molecular-weight Glu-ureido-based PSMA inhibitors. In general, the class of ureabased PSMA inhibitors was first described by Kozikowski et al (9,10), building on the work of Jackson et al (11,12), and introduced as a peptidomimetic counterpart of the most abundant peptidyl neurotransmitter, N-acetyl-L-aspartyl-L-glutamate (Fig. 1).…”

Triazole Appending Agent (TAAG): A New Synthon for Preparing Iodine-Based Molecular Imaging and Radiotherapy Agents

“…26,27 The glu-urea-lys construct has been derivatized with different radioisotopes including iodoaryl compounds and was therefore an attractive agent for assessing the iodotriazole synthon. 28−32 Methyl ester 2a was coupled to tBu protected glu-urea-lys at 60°C for 24 h, and the product 5a was isolated in 73% yield.…”