Glutamate Carboxypeptidase II in Diagnosis and Treatment of Neurologic Disorders and Prostate Cancer

Abstract

Glutamate carboxypeptidase II (GCPII) is a membrane-bound binuclear zinc metallopeptidase with the highest expression levels found in the nervous and prostatic tissue. Throughout the nervous system, glia-bound GCPII is intimately involved in the neuron-neuron and neuron-glia signaling via the hydrolysis of N-acetylaspartylglutamate (NAAG), the most abundant mammalian peptidic neurotransmitter. The inhibition of the GCPII-controlled NAAG catabolism has been shown to attenuate neurotoxicity associated with enhanced glutamate transmission and GCPII-specific inhibitors demonstrate efficacy in multiple preclinical models including traumatic brain injury, stroke, neuropathic and inflammatory pain, amyotrophic lateral sclerosis, and schizophrenia. The second major area of pharmacological interventions targeting GCPII focuses on prostate carcinoma; GCPII expression levels are highly increased in androgen-independent and metastatic disease. Consequently, the enzyme serves as a potential target for imaging and therapy. This review offers a summary of GCPII structure, physiological functions in healthy tissues, and its association with various pathologies. The review also outlines the development of GCPII-specific small-molecule compounds and their use in preclinical and clinical settings.

Response and Tolerability of a Single Dose of177Lu-PSMA-617 in Patients with Metastatic Castration-Resistant Prostate Cancer: A Multicenter Retrospective Analysis

“…Glutamate carboxypeptidase II-now frequently called PSMA-is a membrane-bound metallopeptidase whose expression is highest in prostate cancer tissue (13). Therefore, PSMA is an ideal target for radioligand therapy.…”

Pharmacokinetics and Pharmacodynamics of the Glutamate Carboxypeptidase II Inhibitor 2-MPPA Show Prolonged Alleviation of Neuropathic Pain through an Indirect Mechanism

“…The neuropeptide N-acetyl-aspartyl glutamate (NAAG) is abundant in both brain and peripheral nervous system, where it appears to serve as a neurotransmitter both as a dipeptide and as a precursor of glutamate. As a dipeptide, it appears to act through mGluR3 receptors to decrease glutamate release (Neale et al, 2011;Ba rinka et al, 2012).…”

“…2-PMPA was shown to possess therapeutic efficacy in various preclinical models, including ischemia (Slusher et al, 1999), spinal cord injury (Long et al, 2005), neuropathic pain (Jackson et al, 2001;Wozniak et al, 2012), cocaine addiction (Xi et al, 2010a;Xi et al, 2010b), and schizophrenia (Olszewski et al, 2008;Zuo et al, 2012). Thus, GCP-II inhibition may provide broad therapeutic utility in neurologic diseases especially where excess glutamate is presumed pathogenic (Rojas et al, 2011;Ba rinka et al, 2012). Although potent and selective, 2-PMPA is not orally available perhaps due to its extreme hydrophilic nature and limited permeability through the gastrointestinal tract.…”

Information about Prostate Cancer for Urologist: Ga-68 Prostate Specific Membrane Antigen Positron Emission Tomography/Computed Tomography Scintigraphy

“…Başlangıçta PSMA'ya karşı geliştirilmiş monoklonal antikorlar, In-111 ve Tc-99m ile işaretlenmiş ve 1990'lı yıllarda Amerika Birleşik Devletleri'nde (ABD) Gıda ve İlaç İdaresi onayı alarak kullanıma girmiştir. Ancak bir makro-molekül olan monoklonal antikorlar, yeteri kadar tümör hücresi içerisine internalize olamadığı için ve görüntüleme teknolojisinin PET/BT sintigrafisi kadar iyi olmadığı için yeterli sensitiviteye ulaşmamış ve çok da geniş bir uygulama alanı bulamamıştır (2). Daha sonra, küçük molekül PSMA inhibitörleri radyofarmasistler tarafından fark edilince F-18, I-123, I-124 ve I-131 gibi radyoaktif maddeler ile işaretlenmiştir (2).…”

“…Ancak bir makro-molekül olan monoklonal antikorlar, yeteri kadar tümör hücresi içerisine internalize olamadığı için ve görüntüleme teknolojisinin PET/BT sintigrafisi kadar iyi olmadığı için yeterli sensitiviteye ulaşmamış ve çok da geniş bir uygulama alanı bulamamıştır (2). Daha sonra, küçük molekül PSMA inhibitörleri radyofarmasistler tarafından fark edilince F-18, I-123, I-124 ve I-131 gibi radyoaktif maddeler ile işaretlenmiştir (2). Son olarak üre temelli PSMA inhibitörü olan Glu-NH-CO-NH-Lys (Ahx) peptidi HBED-CC bağlaç molekülü kullanılarak bir jeneratör ürünü olan Ga-68 ile işaretlenmiştir (4,5).…”