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

专注于抗A-β疗法治疗阿尔茨海默病(AD)的试验一直未能取得成功，这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这样的靶点是神经炎症，它越来越被认为是阿尔茨海默病发病机制中的关键介质。我们使用体内成像和正电子发射断层扫描(PET)来评估神经胶质细胞的活动，这种活动在AD中被破坏，在AD中，神经炎症，特别是小胶质细胞被慢性激活，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形成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，它通过结合巨噬细胞集落刺激因子-1受体(CSF1R)而特异性地作用于小胶质细胞。尸检研究表明，AD患者脑内CSF1R的表达显著增加。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，在非人类灵长类动物的神经炎症和死后人脑(健康和AD)模型中。最终，我们将使用这种药物来开发治疗阿尔茨海默病神经炎性成分的药物。 作为验证的第一步，拟议的成像项目解决了在神经炎症条件下CSF1R在狒狒脑内的可用性和分布的测量(目标1)。在分级方法中，我们将使用[18F]JHU12809完成临床前研究，包括放射性代谢评估和剂量估算计算(目标2)、放射合成的优化和自动化(目标3)以及死后健康和AD大脑中CSF1R密度的测定(目标4)。我们已经获得了EED所需的毒理学研究的独立资金。这个项目完成后，我们将验证针对CSF1R的18F标记放射性示踪剂，CSF1R越来越被认为是脑内小胶质细胞的特定标记，准备应用于AD和其他迄今未在人类受试者中直接和非侵入性研究的潜在情况。值得注意的是，建议研究中的测试文章[18F]JHU12809甚至比我们最近的领先产品[11C]CPPC更具体地适用于CSF1R。[18F]JHU12809更长的物理半衰期将通过学术和行业合作实现广泛的翻译和传播。

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.