Metabotropic glutamate 1 receptors (mGluR1) are G-protein coupled receptors and are expressed in many central nervous system regions, especially in cerebellum, cerebral cortex, hippocampus and thalamus. Several studies have shown that mGluR1 plays a crucial role in synaptic plasticity, learning and memory and motor coordination. Over activation of this receptor has been implicated in neurological and psychiatric disorders such as ischemia, epilepsy, anxiety, depressive disorders, multiple sclerosis and neuropathic pain. As a result mGluR1s have been the targets of intensive drug development research. A Positron Emission Tomography (PET) ligand would be a biological marker to detect alterations in mGluR1 in vivo and non-invasively. In view of this many groups have attempted to develop a specific PET tracer with limited success. Therefore, the objective of the proposed study is to develop a PET tracer to non-invasively monitor in vivo binding to the mGluR1 from rats to non-human primates. We propose three new mGluR1 antagonists 1, 2, and 3 (Figure 2) as candidates for PET tracer development based on their excellent affinity to mGluR1, adequate logP values that allow facile entry to brain, availability of suitable labeling sites and promising in vivo pharmacology data available. We accomplished the synthesis of [11C] 1 in good yield and specific activity. Our initial autoradiography studies in slide mounted sections of postmortem human brain resulted in specific binding of [11C] 1 to mGluR1 enriched brain regions (section 4). In this application, therefore, we propose to complete the characterization of [11C] 1 through rats and baboon studies such that the next phase of work would be related to use in man. [11C] 1 is a promising lead tracer and its analogues 2 and 3 are also selected as alternate compounds. Blocking studies with the known mGluR1 antagonist JNJ16259685 will be performed to obtain specific binding in rats and baboon. [11C] 2 and [11C] 3 will also be synthesized as alternative ligands and studied successively if [11C] 1 fails to meet the criteria of a specific PET tracer for mGluR1. The optimal PET tracer will be identified for modeling studies and to develop methods for the quantification of mGluR1 in man. The selection criteria of candidate PET tracers for testing, and the strategies proposed for the identification of the most successful tracer is given in sections 5. At the end of the proposed studies we anticipate to have a PET tracer as potential tool for in vivo human studies of mGluR1, and to obtain occupancy of drugs that have affinity to mGluR1.
Metabotropic glutamate 1 receptor (mGluR1s) are involved in the pathophysiology of epilepsy, ischemia, anxiety, depression and neuropathic pain and by using Positron Emission Tomography (PET) it is possible to measure changes in a receptor system in vivo non-invasively and quantitatively in molecular level. To date there is no successful PET tracer for the /in vivo/ quantification of mGluR1. Therefore, we are committed to develop a specific PET tracer for mGluR1 as a potential tool for human studies of psychiatric illnesses and for novel drug development
| Prabhakaran, Jaya; Majo, Vattoly J; Milak, Matthew S et al. (2010) Synthesis, in vitro and in vivo evaluation of [11C]MMTP: a potential PET ligand for mGluR1 receptors. Bioorg Med Chem Lett 20:3499-501 |
