F-18 labelled PET tracer for imaging macrophage colony stimulating factor 1 receptor (CSF1R) in neuroinflammation

针对阿尔茨海默病（AD）的抗a β疗法的试验尚未取得成功，因此需要考虑其他临床靶点或多靶点方法。我们一直关注的一个目标是神经炎症，它越来越被认为是阿尔茨海默病发病机制的关键媒介。我们使用正电子发射断层扫描（PET）在体内成像来评估神经胶质细胞的活性，这种活性在阿尔茨海默病中被破坏，其中神经炎症，特别是小胶质细胞，被慢性激活以促进持续的促炎环境。我们的同事已经证明，小胶质细胞诱导星形胶质细胞产生A1促炎表型，这对神经元是有毒的。我们最近发现了第一种也是唯一一种PET显像剂[11C]CPPC，它通过与巨噬细胞集落刺激因子-1受体（CSF1R）结合，对小胶质细胞具有特异性。死后研究表明，AD患者脑CSF1R的表达高度增加。我们目前的目标是验证第二代更具商业可行性的CSF1R PET显像剂[18F]JHU12809在神经炎症和死后人脑（健康和AD）的非人类灵长类动物模型中的有效性。最终，我们将使用这种药物来开发针对阿尔茨海默病神经炎症成分的药物。

Success has eluded trials that have focused on anti-Aβ 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.