Troriluzole inhibits methamphetamine place preference in rats and normalizes methamphetamine-evoked glutamate carboxypeptidase II (GCPII) protein levels in the mesolimbic pathway.

Riluzole, approved to manage amyotrophic lateral sclerosis, is mechanistically unique among glutamate-based therapeutics because it reduces glutamate transmission through a dual mechanism (i.e., reduces glutamate release and enhances glutamate reuptake). The profile of riluzole is favorable for normalizing glutamatergic dysregulation that perpetuates methamphetamine (METH) dependence, but pharmacokinetic and metabolic liabilities hinder repurposing. To mitigate these limitations, we synthesized troriluzole (TRLZ), a third-generation prodrug of riluzole, and tested the hypothesis that TRLZ inhibits METH hyperlocomotion and conditioned place preference (CPP) and normalizes METH-induced changes in mesolimbic glutamate biomarkers. TRLZ (8, 16 mg/kg) reduced hyperlocomotion caused by METH (1 mg/kg) without affecting spontaneous activity. TRLZ (1, 4, 8, 16 mg/kg) administered during METH conditioning (0.5 mg/kg x 4 d) inhibited development of METH place preference, and TRLZ (16 mg/kg) administered after METH conditioning reduced expression of CPP. In rats with established METH place preference, TRLZ (16 mg/kg) accelerated extinction of CPP. In cellular studies, chronic METH enhanced mRNA levels of glutamate carboxypeptidase II (GCPII) in the ventral tegmental area (VTA) and prefrontal cortex (PFC). Repeated METH also caused enhancement of GCPII protein levels in the VTA that was prevented by TRLZ (16 mg/kg). TRLZ (16 mg/kg) administered during chronic METH did not affect brain or plasma levels of METH. These results indicate that TRLZ, already in clinical trials for cerebellar ataxia, reduces development, expression and maintenance of METH CPP. Moreover, normalization of METH-induced GCPII levels in mesolimbic substrates by TRLZ points toward studying GCPII as a therapeutic target of TRLZ.

Prostate-Specific Membrane Antigen (PSMA) Theranostics for Treatment of Oligometastatic Prostate Cancer.

Theranostics, a combination of therapy and diagnostics, is a field of personalized medicine involving the use of the same or similar radiopharmaceutical agents for the diagnosis and treatment of patients. Prostate-specific membrane antigen (PSMA) is a promising theranostic target for the treatment of prostate cancers. Diagnostic PSMA radiopharmaceuticals are currently used for staging and diagnosis of prostate cancers, and imaging can predict response to therapeutic PSMA radiopharmaceuticals. While mainly used in the setting of metastatic, castrate-resistant disease, clinical trials are investigating the use of PSMA-based therapy at earlier stages, including in hormone-sensitive or hormone-naïve prostate cancers, and in oligometastatic prostate cancers. This review explores the use of PSMA as a theranostic target and investigates the potential use of PSMA in earlier stage disease, including hormone-sensitive metastatic prostate cancer, and oligometastatic prostate cancer.

Current status of radioligand therapy and positron-emission tomography with prostate-specific membrane antigen.

Prostate-specific membrane antigen (PSMA) is a transmembrane glycoprotein highly expressed by prostate cancer cells. PSMA-based radioligand therapy (RLT) emerged as a promising therapeutic option for prostate cancer in the early 2000s, and has been clinically validated with great enthusiasm during these past two decades. Last year, the European Association of Nuclear Medicine (EANM) published the procedure guidelines for the safe clinical practice of Lutetium-177 (177Lu)-labelled PSMA RLT. In addition, PSMA RLT with alpha-ray-emitting radioisotopes has been also developed recently. Following the clinical use of 177Lu-PSMA RLT, PSMA-targeted positron-emission tomography (PET) with Gallium-68 (68Ga) has been performed inevitably for "theranostics" for the last decade; prostate cancer is going to be treated with PSMA-RLT based on the diagnosis by PSMA-PET. Furthermore, the diagnostic usefulness of 68Ga-PSMA PET has been documented in various diseases beyond prostate cancer more recently. Regrettably, Japan is behind European countries and the United States in this field, and has just made a belated start of their clinical trials. In this review article, we briefly overviewed the current status of PSMA RLT and PSMA PET. We hope that this topic will be a particular focus of attention for most ANM readers in Japan, and that our efforts will help to facilitate the early approval of PSMA RLT and PSMA PET by the Japanese government even if only slightly.

Copper, PET/CT and prostate cancer: a systematic review of the literature.

Copper is an essential element that plays an important role in both cancer development and growth. Indeed, high levels of copper have been found in prostate cancer (PCa), and this finding have paved the way for the use of this element as a target for positron emission tomography (PET) imaging. Copper64 (64Cu) can be used alone, as 64CuCl2, and also as a precursor for the in-vitro radio-labelling of specific carriers for PET imaging in PCa, (e.g. associated to prostate-specific membrane antigen: PSMA). The use of 64Cu-PSMA can yield late acquisitions in which PET images are characterized by a higher target-to-background ratio. At the same time, the shorter positron range of 64Cu provides high spatial resolution, which leads to better detection of small lesions. In this context, the aim of this review was to systematically review studies evaluating the identification of PCa in humans by means of 64CuCl2 and other PET tracers radio-labelled with 64Cu.

Treatment outcomes of metastasis-directed treatment using 68Ga-PSMA-PET/CT for oligometastatic or oligorecurrent prostate cancer: Turkish Society for Radiation Oncology group study (TROD 09-002).

PURPOSE: The aim of this study was to evaluate the outcomes of 68Ga prostate-specific membrane antigen (68Ga-PSMA) positron-emission tomography (PET)/CT-based metastasis-directed treatment (MDT) for oligometastatic prostate cancer (PC). METHODS: In this multi-institutional study, clinical data of 176 PC patients with 353 lesions receiving MDT between 2014 and 2019 were retrospectively evaluated. All patients had biopsy proven PC with ≤5 metastases detected with 68Ga-PSMA-PET/CT. MDT was delivered with conventional fractionation or stereotactic body radiotherapy (SBRT) techniques. CTCAE v4.0 was used for acute and RTOG/EORTC Late Radiation Morbidity Scoring Schema was used for late toxicity evaluation. RESULTS: At the time of MDT, 59 patients (33.5%) had synchronous and 117 patients (66.5%) had metachronous metastases. Median number of metastases was one and the MDT technique was SBRT in 73.3% patients. The 2­year overall survival (OS) and progression-free survival (PFS) rates were 87.6% and 63.1%, respectively. With a median follow-up of 22.9 months, 9 patients had local recurrence at the irradiated site. The 2­year local control rate at the treated oligometastatic site per patient was 93.2%. In multivariate analysis, an increased number of oligometastases and untreated primary PC were negative predictors for OS; advanced clinical tumor stage, untreated primary PC, BED3 value of ≤108 Gy, and MDT with conventional fractionation were negative predictors for PFS. No patient experienced grade ≥3 acute toxicity, but one patient had a late grade 3 toxicity of compression fracture after spinal SBRT. CONCLUSION: 68Ga-PSMA-PET/CT-based MDT is an efficient and safe treatment for oligometastatic PC patients. Proper patient selection might improve treatment outcomes.

Early Prostate-Specific Antigen Changes and Clinical Outcome After 177Lu-PSMA Radionuclide Treatment in Patients with Metastatic Castration-Resistant Prostate Cancer.

Prostate-specific antigen (PSA) is widely used to monitor treatment response in patients with metastatic castration-resistant prostate cancer. However, PSA measurements are considered only after 12 wk of treatment. We aimed to evaluate the prognostic value of early PSA changes after 177Lu-labeled prostate-specific membrane antigen (177Lu-PSMA) radionuclide treatment in metastatic castration-resistant prostate cancer patients. Methods: Men who were treated with 177Lu-PSMA under a compassionate-access program at our institution and had available PSA values at baseline and at 6 wk after treatment initiation were included in this retrospective analysis. Patients were assigned to 3 groups on the basis of PSA changes: response (≥30% decline), progression (≥25% increase), and stable (<30% decline and <25% increase). The coprimary endpoints were overall survival and imaging-based progression-free survival. The secondary endpoints were PSA changes at 12 wk and PSA flare-up. Results: We identified 124 eligible patients with PSA values at 6 wk. A greater than or equal to 30% decline in PSA at 6 wk was associated with longer overall survival (median, 16.7 mo; 95% CI, 14.4-19.0) than stable PSA (median, 11.8 mo; 95% CI, 8.6-15.1) (P = 0.007) or PSA progression (median, 6.5 mo; 95% CI, 5.2-7.8) (P < 0.001). Patients with a greater than or equal to 30% decline in PSA at 6 wk also had a lower risk of imaging-based progression than patients with stable PSA (hazard ratio, 0.60; 95% CI, 0.38-0.94) (P = 0.02), whereas patients with PSA progression had a higher risk of imaging-based progression than patients with stable PSA (hazard ratio, 3.18; 95% CI, 1.95-5.21) (P < 0.001). The percentage changes in PSA at 6 and 12 wk were highly associated (r = 0.90; P < 0.001). Of 31 patients who experienced early PSA progression at 6 wk, 29 (94%) showed biochemical progression at 12 wk. Overall, only 1 (3%) of 36 patients with PSA progression at 6 wk achieved any PSA decline at 12 wk (1% of the entire cohort). The limitations of the study included its retrospective nature and the single-center experience. Conclusion: PSA changes at 6 wk after 177Lu-PSMA initiation are an early indicator of long-term clinical outcome. Patients with PSA progression after 6 wk of treatment could benefit from a very early decision to switch treatment. PSA flare-up during 177Lu-PSMA treatment is very uncommon. Prospective studies are now warranted to validate our findings and potentially inform clinicians earlier on the effectiveness of 177Lu-PSMA.

Efecto positivo del tratamiento con Actinio 225-PSMA sobre el estado funcional ECOG: informe del caso de un paciente con cáncer de próstata en estadio IV resistente a la castración / Positive effect of Actinium 225-PSMA treatment on ECOG performance status: A case report on a patient with castration resistant stage IV prostate carcinoma

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Radionuclide Therapy With 177Lu-PSMA in a Case of Metastatic Adenoid Cystic Carcinoma of the Parotid.

In vivo prostate-specific membrane antigen (PSMA) overexpression creates an opportunity for PSMA-directed theranostic approach in adenoid cystic carcinoma of the parotid. Herein, we illustrate a patient with metastatic PSMA-directed theranostic approach in adenoid cystic carcinoma of the parotid who had intense PSMA uptake on metastatic lesions, followed by radionuclide therapy with Lu-PSMA.

Salvage Radiopeptide Therapy of Advanced Castrate-Resistant Prostate Cancer with Lutetium-177-Labeled Prostate-Specific Membrane Antigen: Efficacy and Safety in Routine Practice.

BACKGROUND: Prostate-specific membrane antigen (PSMA)-based radiopeptide/radioligand therapy represents a rapidly expanding field in the management of metastatic castrate-resistant prostate cancer (mCRPC). However, there remains concern for the development of significant toxicities in heavily pretreated patients. In this study, the authors present their local experience, with respect to efficacy and toxicity, of 22 consecutive patients treated with lutetium-177-DOTAGA-(I-y)fk(Sub-KuE) or 177Lu-PSMA I&T radioimmunotherapy for progressive mCRPC, followed up over 1 year. MATERIALS AND METHODS: All patients had progressive mCRPC, an European Cooperative Oncology Group (ECOG) ≤2 with adequate bone marrow and liver function. 177Lu-PSMA I&T therapy was administered at 8-week intervals with a mean prescribed activity of 5.5 GBq (gigabecquerel) per patient. RESULTS: Twenty patients had evaluable results, median age of 71 years, and median duration of follow-up of 17 months. Three patients (15%) experienced a G1/2 myelotoxicity and four (20%) G3/4. No incidences of myelodysplasia/acute leukemia have been identified. All toxicities were self-limiting. Baseline cytopenia was predictive of the development of subsequent G3/4 myelotoxicity (p = 0.0035). Eight patients (40%) experienced an objective PSA response, with a median time to response of 15 weeks. The median time to PSA progression was not reached. Patients receiving three cycles of therapy were statistically more likely to experience a disease response when compared to those treated with one, two, or four cycles (p < 0.0001). CONCLUSIONS: 177Lu-PSMA I&T radioimmunotherapy of progressive mCRPC is safe and effective with three cycles being the potential optimal number for determining long-term disease response.

Near-Infrared Photoimmunotherapy Targeting Prostate Cancer with Prostate-Specific Membrane Antigen (PSMA) Antibody.

Prostate-specific membrane antigen (PSMA) is a membrane protein that is overexpressed manifold in prostate cancer and provides an attractive target for molecular therapy. Near-infrared photoimmunotherapy (NIR-PIT) is a highly selective tumor treatment that employs an antibody-photoabsorber conjugate (APC). Here, we describe the efficacy of NIR-PIT, using a fully human IgG1 anti-PSMA monoclonal antibody (mAb), conjugated to the photoabsorber, IR700DX, in a PSMA-expressing PC3 prostate cancer cell line. Anti-PSMA-IR700 showed specific binding and cell-specific killing was observed after exposure of the cells to NIR light in vitro In the in vivo study, anti-PSMA-IR700 showed high tumor accumulation and high tumor-background ratio. Tumor-bearing mice were separated into 4 groups: (i) no treatment; (ii) 100 µg of anti-PSMA-IR700 i.v.; (iii) NIR light exposure; (iv) 100 µg of anti-PSMA-IR700 i.v., NIR light exposure was administered. These were performed every week for up to 3 weeks. Tumor growth was significantly inhibited by NIR-PIT treatment compared with the other control groups (P < 0.001), and significantly prolonged survival was achieved (P < 0.0001 vs. other control groups). More than two thirds of tumors were cured with NIR-PIT. In conclusion, the anti-PSMA antibody is suitable as an APC for NIR-PIT. Furthermore, NIR-PIT with the anti-PSMA-IR700 antibody is a promising candidate of the treatment of PSMA-expressing tumors and could be readily translated to humans.Implications: NIR-infrared photoimmunotherapy (NIR-PIT) using a fully human anti-PSMA-IR700 conjugate showed potential therapeutic effects against a PSMA-expressing prostate cancer that is readily translated to humans. Mol Cancer Res; 15(9); 1153-62. ©2017 AACR.

Lutetium-177-labelled anti-prostate-specific membrane antigen antibody and ligands for the treatment of metastatic castrate-resistant prostate cancer: a systematic review and meta-analysis.

BACKGROUND: Promising therapeutic results of the prostate-specific membrane antigen (PSMA) ligand have been shown when labelling with lutetium-177 (177Lu). We performed a systematic review and meta-analysis to assess the therapeutic response of 177Lu-PSMA in the treatment of metastatic castration-resistant prostate cancer (mCRPC). METHODS: A systematic review was conducted using electronic databases up to December 2016. Two reviewers independently extracted data and assessed methodological quality. The main outcome of interest was antitumour biochemical response of 177Lu-PSMA, analysing two measures: 'any PSA decline' and '>50% decline' from baseline. A random-effects meta-analysis was used to calculate the pooled proportion across studies. The I2 statistic was calculated in each case to investigate the extent of heterogeneity across the studies. A sensitivity analysis was conducted removing two studies, which were presented as abstracts and proportions were summarised by chemical type (177Lu-J591/DKZ/I&T). All analyses were conducted using Stata v14. RESULTS: A total of 10 studies were included in the analysis giving a total sample size of 369, 220 (of 334 analysable) experienced any PSA decline. The pooled proportion of patients with any PSA decline was 68% (95% confidence interval (CI): 61-74). The I2 statistic was 39.1% (P=0.11) suggesting minor heterogeneity between results. The pooled proportion of patients with >50% PSA decline was 37% (95% CI: 22-52). The I2 statistic was 91.0% (P<0.001) suggesting substantial heterogeneity between results. On subgroup analysis, a higher proportion of patients in the 177Lu-DKZ/I&T subgroup had a PSA decline >50%, however, it can be seen that the 177Lu-DKZ/I&T subgroup had a substantial amount of heterogeneity across studies. CONCLUSIONS: This review suggests promising early results for the treatment of mCRPC, especially from patients treated with the more recently developed radioligands. Overall, our meta-analysis showed that approximately two-thirds of patients had a biochemical response. Randomised-controlled trials would be necessary to verify its effectiveness against current systemic therapies and create an ideal treatment protocol.

Investigating the Effect of Ligand Amount and Injected Therapeutic Activity: A Simulation Study for 177Lu-Labeled PSMA-Targeting Peptides.

In molecular radiotherapy with 177Lu-labeled prostate specific membrane antigen (PSMA) peptides, kidney and/or salivary glands doses limit the activity which can be administered. The aim of this work was to investigate the effect of the ligand amount and injected activity on the tumor-to-normal tissue biologically effective dose (BED) ratio for 177Lu-labeled PSMA peptides. For this retrospective study, a recently developed physiologically based pharmacokinetic model was adapted for PSMA targeting peptides. General physiological parameters were taken from the literature. Individual parameters were fitted to planar gamma camera measurements (177Lu-PSMA I&T) of five patients with metastasizing prostate cancer. Based on the estimated parameters, the pharmacokinetics of tumor, salivary glands, kidneys, total body and red marrow was simulated and time-integrated activity coefficients were calculated for different peptide amounts. Based on these simulations, the absorbed doses and BEDs for normal tissue and tumor were calculated for all activities leading to a maximal tolerable kidney BED of 10 Gy2.5/cycle, a maximal salivary gland absorbed dose of 7.5 Gy/cycle and a maximal red marrow BED of 0.25 Gy15/cycle. The fits yielded coefficients of determination > 0.85, acceptable relative standard errors and low parameter correlations. All estimated parameters were in a physiologically reasonable range. The amounts (for 25-29 nmol) and pertaining activities leading to a maximal tumor dose, considering the defined maximal tolerable doses to organs of risk, were calculated to be 272±253 nmol (452±420 µg) and 7.3±5.1 GBq. Using the actually injected amount (235±155 µg) and the same maximal tolerable doses, the potential improvement for the tumor BED was 1-3 fold. The results suggest that currently given amounts for therapy are in the appropriate order of magnitude for many lesions. However, for lesions with high binding site density or lower perfusion, optimizing the peptide amount and activity might improve the tumor-to-kidney and tumor-to-salivary glands BED ratio considerably.

Systemic Radioligand Therapy with (177)Lu Labeled Prostate Specific Membrane Antigen Ligand for Imaging and Therapy in Patients with Metastatic Castration Resistant Prostate Cancer.

PURPOSE: We report our initial clinical experience with ß -emitting (177)Lu-PSMA-I&T ((177)Lu labeled prostate specific membrane antigen ligand for imaging and therapy) for systemic treatment of metastatic castration resistant prostate cancer. MATERIALS AND METHODS: Patients with metastatic castration resistant prostate cancer who experienced treatment failure with chemotherapy and novel androgen receptor targeted therapy were treated for 8 weeks with up to 4 cycles of (177)Lu-PSMA-I&T. We report safety data, the antitumor response with prostate specific antigen decreases and the radiographic tumor response as well as the clinical outcome with changes in ECOG (Eastern Cooperative Oncology Group) performance status and pain severity. RESULTS: The first 3 patients were treated with a lower activity of 3.7 GBq in cycle 1. Due to a favorable safety profile the activity was increased to 7.4 GBq in 19 subsequent patients who completed a total of 40 cycles. With the higher activity no grade 3/4 toxicities were observed. The main nonhematological and hematological grade 1/2 toxicities were dry mouth in 7 patients (37%), anemia in 6 (32%) and thrombopenia in 5 (25%). The proportion of patients who achieved a maximum prostate specific antigen decrease of 30% or greater, 50% or greater and 90% or greater was 56%, 33% and 11%, respectively. Combined assessment of bone and soft tissue metastases showed complete remission in 5% of patients, stable disease in 63% and progressive disease in 32%. ECOG performance status improved or was stable in 74% of patients. Of men with bone pain 58% achieved complete resolution or reduced pain. CONCLUSIONS: Radioligand therapy with (177)Lu-PSMA-I&T appears to be safe and active in heavily pretreated patients with metastatic castration resistant prostate cancer.

177Lu-Labeled Prostate-Specific Membrane Antigen Radioligand Therapy of Metastatic Castration-Resistant Prostate Cancer: Safety and Efficacy.

UNLABELLED: The objective of this study was to analyze the safety and efficacy of the (177)Lu-labeled DOTAGA-based prostate-specific membrane antigen (PSMA) ligand (177)Lu-DOTAGA-(I-y)fk(Sub-KuE) ((177)Lu-PSMA) in patients with metastatic castration-resistant prostate cancer (mCRPC). METHODS: Fifty-six mCRPC patients underwent PSMA radioligand therapy (RLT) with (177)Lu-PSMA. (68)Ga-PSMA-(N,N'-bis-[2-hydroxy-5-(carboxyethyl)benzyl]ethylenediamine-N,N'-diacetic acid) ((68)Ga-PSMA) PET/CT was used for patient selection and follow-up after PSMA RLT. Hematologic status, renal function, and serum prostate-specific antigen levels were documented before and after therapy. Dosimetry was performed in 30 patients. RESULTS: (177)Lu-PSMA demonstrated high absorbed tumor doses (median, 3.3 mGy/MBq) compared with the levels in normal organs. Parotid glands received higher doses (1.3 mGy/MBq) than kidneys (0.8 mGy/MBq). All patients tolerated the therapy without any acute adverse effects. Except for mild reversible xerostomia in 2 patients, no long-term side effects were observed. There was a small but statistically significant reduction in erythrocyte and leukocyte counts; only the reduction in erythrocyte counts decreased slightly below the reference range. No thrombocytopenia occurred. The severity of pain was significantly reduced in 2 of 6 patients (33.3%). A decrease in prostate-specific antigen levels was noted in 45 of 56 patients (80.4%). Of 25 patients monitored for at least 6 mo after 2 or more PSMA RLT cycles, a molecular response evaluation ((68)Ga-PSMA PET/CT) revealed partial remission in 14, stable disease in 2, and progressive disease in 9 patients. Contrast-enhanced CT revealed partial remission in 5, stable disease in 13, and progressive disease in 7 patients. The median progression-free survival was 13.7 mo, and the median overall survival was not reached during follow-up for 28 mo. CONCLUSION: PSMA RLT with (177)Lu-PSMA is feasible, safe, and effective in end-stage progressive mCRPC with appropriate selection and follow-up of patients by (68)Ga-PSMA PET/CT through application of the concept of theranostics.

Ipilimumab in the treatment of prostate cancer.

Ipilimumab (Yervoy(®); Bristol-Myers Squibb, NY, USA) is a fully human monoclonal antibody targeting CTLA-4 and is approved for the treatment of metastatic melanoma. Preclinical and clinical studies have shown its activity in a number of different cancer types, including prostate cancer. Recently, the results from a Phase III study of ipilimumab in prostate cancer patients with prior docetaxel therapy were reported. Although the study did not meet the primary end point of improved overall survival, prespecified subset analyses suggested that ipilimumab may be more active in men with lower disease burden, which suggests that immunotherapy should be tested early in men with castration-refractory prostate cancer. Immune-related adverse events are common and most can be well managed with standard immunosuppressive algorithms.

DNA fusion-gene vaccination in patients with prostate cancer induces high-frequency CD8(+) T-cell responses and increases PSA doubling time.

We report on the immunogenicity and clinical effects in a phase I/II dose escalation trial of a DNA fusion vaccine in patients with prostate cancer. The vaccine encodes a domain (DOM) from fragment C of tetanus toxin linked to an HLA-A2-binding epitope from prostate-specific membrane antigen (PSMA), PSMA(27-35). We evaluated the effect of intramuscular vaccination without or with electroporation (EP) on vaccine potency. Thirty-two HLA-A2(+) patients were vaccinated and monitored for immune and clinical responses for a follow-up period of 72 weeks. At week 24, cross-over to the immunologically more effective delivery modality was permitted; this was shown to be with EP based on early antibody data, and subsequently, 13/15 patients crossed to the +EP arm. Thirty-two HLA-A2(-) control patients were assessed for time to next treatment and overall survival. Vaccination was safe and well tolerated. The vaccine induced DOM-specific CD4(+) and PSMA(27)-specific CD8(+) T cells, which were detectable at significant levels above baseline at the end of the study (p = 0.0223 and p = 0.00248, respectively). Of 30 patients, 29 had a measurable CD4(+) T-cell response and PSMA(27)-specific CD8(+) T cells were detected in 16/30 patients, with or without EP. At week 24, before cross-over, both delivery methods led to increased CD4(+) and CD8(+) vaccine-specific T cells with a trend to a greater effect with EP. PSA doubling time increased significantly from 11.97 months pre-treatment to 16.82 months over the 72-week follow-up (p = 0.0417), with no clear differential effect of EP. The high frequency of immunological responses to DOM-PSMA(27) vaccination and the clinical effects are sufficiently promising to warrant further, randomized testing.

Phencyclidine and dizocilpine induced behaviors reduced by N-acetylaspartylglutamate peptidase inhibition via metabotropic glutamate receptors.

BACKGROUND: N-methyl-D-aspartate (NMDA) receptor open channel blockers phencyclidine (PCP) and dizocilpine (MK-801) elicit schizophrenia-like symptoms in humans and in animal models. Group II metabotropic glutamate receptor agonists reverse the behavioral effects of PCP and MK-801 in animal models. N-acetylaspartylglutamate (NAAG), the third most prevalent neurotransmitter in the mammalian nervous system, is a selective group II metabotropic glutamate receptor agonist. We previously reported that ZJ43, a potent inhibitor of the enzymes that inactivate synaptically released NAAG, reduced motor and stereotypic effects of PCP in the rat. METHODS: To confirm the efficacy of NAAG peptidase inhibition in decreasing motor behaviors induced by PCP and MK-801, ZJ43 was tested in additional schizophrenia models. RESULTS: ZJ43 reduced MK-801-induced motor activation in a mouse model that has been used to characterize the efficacy of a wide range of pharmacotherapies for this human disorder. In a second mouse strain, the peptidase inhibitor reduced PCP-induced stereotypic movements. ZJ43 also reduced PCP-induced negative symptoms in a resident-intruder assay. The group II metabotropic glutamate receptor antagonist, LY341495, blocked the effect of NAAG peptidase inhibition in these mouse models of positive and negative PCP- and MK-801-induced behaviors. Additionally, LY341495 alone increased some PCP-induced behaviors suggesting that normal levels of NAAG act to moderate the effect of PCP via a group II mGluR. CONCLUSIONS: These data support the proposal that NAAG peptidase inhibition and elevation of synaptic NAAG levels represent a new therapeutic approach to treating the positive and negative symptoms of schizophrenia that are modeled by open channel NMDA receptor antagonists.