Success has eluded trials that have focused on anti-A? therapies for Alzheimer?s disease (AD), necessitating consideration of other clinical targets or multi-target approaches. One such target on which we have been focusing is neuroinflammation, which is increasingly recognized as a key mediator in the pathogenesis of AD. We have used imaging in vivo with positron emission tomography (PET) to assess glial cell activity, which is disrupted in AD, where neuroinflammation, and in particular microglia, are chronically activated to promote a continually pro-inflammatory milieu. Our colleagues have shown that microglia induce astrocytes to an A1 pro-inflammatory phenotype that is toxic to neurons. We have recently discovered the first and only PET imaging agent, [11C]CPPC, that is specific for microglia by engaging the macrophage colony stimulating factor-1 receptor (CSF1R). Post-mortem studies have shown highly increased expression of cerebral CSF1R in patients with AD. Our present goal is to validate a second-generation, more commercially viable CSF1R PET imaging agent, [18F]JHU12809, in a non-human primate model of neuroinflammation and post-mortem human brain (healthy and AD). Ultimately we will use this agent to enable development of drugs that address the neuroinflammatory component of AD. As an initial step toward validation, the proposed imaging project addresses measurement of the availability and distribution of CSF1R within the baboon brain under neuroinflammatory conditions (Aim 1). In a graded approach we will complete pre-clinical studies with [18F]JHU12809 including assessment of radiometabolites and calculation of dosimetry estimates (Aim 2), optimization and automation of the radiosynthesis (Aim 3) and determination of CSF1R density in post-mortem healthy and AD brains (Aim 4). We have obtained independent funding for the toxicology studies also needed for the eIND. Upon completion of this project we will have validated an 18F-labeled radiotracer targeting CSF1R, increasingly recognized as a specific marker of microglia within the brain, ready to be applied to AD and potentially other conditions not heretofore studied directly and non-invasively in human subjects. Notably, [18F]JHU12809, the test article in the proposed studies, is even more specific for CSF1R than our recent lead, [11C]CPPC. The longer physical half-life of [18F]JHU12809 will enable widespread translation and dissemination through academic and industry collaboration.
The objective of this project is pre-clinical validation of [18F]JHU12809 for PET imaging of macrophage colony stimulating factor 1 receptor (CSF1R) in a non-human primate model of neuroinflammation. CSF1R is a microglia-specific binding site and has been implicated in the pathophysiology of various neuroinflammatory disorders including Alzheimer?s disease, multiple sclerosis, brain cancer and traumatic brain injury. Measurement of CSF1R by PET in human brain would greatly accelerate understanding of the neuroinflammatory aspects of these disorders.
