Human exposure to anthropogenic or naturally occurring chemicals contributes to the incidence of neurological disease. To estimate and minimize the human risk of neurological disease from chemical exposure, it is important to identify whether a chemical, or class of chemicals, produces neurotoxicity and its regional specificity and mechanism of action. Biomarkers of neurotoxicity permit evaluation of exposure to an agent (i.e., dose) and the vulnerability of specific brain structures and cell populations, such as neurons and glial cells, to damage (i.e., effect). A useful approach is to identify marker proteins of neuronal or glial origin that are sensitive to change as a result of neurotoxic insult. Our approach to the development of a biomarker of neurotoxicity focuses on the peripheral benzodiazepine receptor (PBR), a glial- specific mitochondrial protein. The rationale for this strategy is that reactive gliosis is one of the earliest and most widespread response of the nervous system to injury. Quantification of a widespread response is important when there is a paucity of knowledge about neuronal targets that may be damaged.
The specific aims of this proposal are: (1) to synthesize the active enantiomer of the PBR-selective ligand PK11195 thus optimizing the detection of PBR expression following exposure to a neurotoxicant; (2) to continue validating the PBR as a biomarker of neurotoxicity using neurotoxicants that affect diverse neuronal targets, as well as determining the glial cell types responsible for the PBR response; (3) to extend the use of the PBR as a biomarker of neurotoxicity from rodent models to non-human primates using brain imaging techniques. The novel aspect of the proposed work is in the use of the PBR as an in vivo biomarker of neurotoxicity using state-of-the- art brain imaging techniques. This is possible because high-affinity and selective ligands for the PBR will be labeled with single-photon or positron-emitting radioisotopes. To the best of our knowledge, this is the first attempt to develop a biomarker of neurotoxicity that will permit the in vivo study of the human and non-human primate brain following environmental or occupational exposure to chemical agents.
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