Recent advances in the drug discovery of metabotropic glutamate receptor 4 (mGluR4) activators for the treatment of CNS and non-CNS disorders.

INTRODUCTION: The metabotropic glutamate receptor type 4 (mGluR4) plays a pivotal role in a plethora of therapeutic areas, as recently demonstrated in preclinical validation studies with several chemical classes of compounds in rodent models of central nervous system (CNS) and peripheral disorders. Activation of mGluR4 with orthosteric agonists, allosteric agonists or pure positive allosteric modulators (PAM) has been postulated to be of broad therapeutic use. AREAS COVERED: The authors address past and current drug discovery efforts, insights and achievements in the field toward the identification of therapeutically promising and emerging class of mGluR4 activators, over the 2005 - 2011 period. Chemical structures, properties and in vivo pharmacological results discussed in the present review were retrieved from public literature including PubMed searches, Thomson Pharma and SciFinder databases searches, conferences, proceedings and posters. EXPERT OPINION: Developing a subtype-selective, orally bioavailable brain penetrant mGluR4 orthosteric agonist remains challenging. Lack of subtype selectivity and low brain penetration has been a common limitation of the first generation of mGluR4 agonist and potentiators. However, significant progress has recently been made with the identification of several double- to single-digit nanomolar mGluR4 PAM having reasonable pharmacokinetic properties, oral bioavailability and brain penetration. The use of such compounds in research has led to advancement in understanding the central role of mGluR4 in multiple neurodegenerative and neuroinflammatory disorders, such as Parkinson's disease and multiple sclerosis. Our understanding of the potential application of mGluR4 as therapeutic target is expected to grow as these compounds advance into preclinical and clinical development.

Quantification of the glycine transporter 1 in rhesus monkey brain using [18F]MK-6577 and a model-based input function.

BACKGROUND: Glycine transporter 1 (GlyT1) inhibitors have emerged as potential treatments for schizophrenia due to their potentiation of NMDA receptor activity by modulating the local concentrations of the NMDA co-agonist glycine. [18F]MK-6577 is a potent and selective GlyT1 inhibitor PET tracer. Although differences in ligand kinetics can be expected between non-human primates and humans, the tracer pre-clinical evaluation can provide valuable information supporting protocol design and quantification in the clinical space. The main objective of this work was to evaluate the in vivo kinetics of [18F]MK-6577 in rhesus monkey brain. Additionally, a method for estimating the tracer input function from the tracer brain tissue kinetics and venous sampling was validated. This technique was applied for determination of the dose-occupancy relationship of a GlyT1 inhibitor in monkey brain. METHODS: Compartmental and Logan graphical analysis were utilized for quantification of the [18F]MK-6577 binding using the measured tracer arterial input function. The stability of the tracer volume of distribution relative to scan length was assessed. The proposed model-based input function method takes advantage of the agreement between the tracer concentration in arterial and venous plasma from ~5 min. The approach estimates the initial peak of the input curve by adding a gamma like function term to the measured venous curve. The parameters of the model function were estimated by simultaneously fitting several brain time activity curves to a compartmental model. RESULTS: Good agreement was found between the model-based and the measured arterial plasma curve and the corresponding distribution volumes. The Logan analysis was the preferred method of analysis providing reliable and stable volume of distribution and occupancy results using a 90 and possibly 60 min scan length. CONCLUSION: The model-based input function method and Logan analysis are well suited for quantification of [18F]MK-6577 binding and GlyT1 occupancy in monkey brain.

The disposition, metabolism, and pharmacokinetics of a selective metabotropic glutamate receptor agonist in rats and dogs.

Compound LY354740 [(+)-2-aminobicyclo[3.1.0]hexane-2,6-dicarboxylic acid], an analog of glutamic acid, is a selective group 2 metabotropic glutamate receptor agonist in clinical development for the treatment of anxiety. Studies have been conducted to characterize the absorption, disposition, metabolism, and excretion of LY354740 in rats and dogs after intravenous bolus or oral administration. Plasma concentrations of LY354740 were measured using a validated gas chromatography/mass spectrometry assay. In rats, LY354740 demonstrated linear pharmacokinetics after oral administration from 30 to 1000 mg/kg. The oral bioavailability of LY354740 was approximately 10% in rats and 45% in dogs. In the dog, food decreased the mean area under the plasma concentration-time curve value by approximately 34%, hence, decreasing the oral bioavailability of the compound. Excretion studies in both rats and dogs indicate that the absorbed drug is primarily eliminated via renal excretion. In addition, tissue distribution in rats showed that the highest levels of radioactivity were in the kidney and gastrointestinal tract, which is consistent with the excretion studies. Metabolism of LY354740 was evaluated in vitro using rat and dog liver microsomes and rat liver slices. In addition, urine and fecal samples from rat and dog excretion studies were profiled using HPLC with radio-detection. These evaluations indicated that neither rats nor dogs metabolized LY354740. In summary, LY354740 is poorly absorbed in rats, moderately absorbed in dogs, and rapidly excreted as unchanged drug in the urine.