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

F-18 标记的 PET 示踪剂,用于神经炎症中巨噬细胞集落刺激因子 1 受体 (CSF1R) 的成像

基本信息

  • 批准号:
    10390394
  • 负责人:
  • 金额:
    $ 59.67万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2020
  • 资助国家:
    美国
  • 起止时间:
    2020-09-15 至 2025-04-30
  • 项目状态:
    未结题

项目摘要

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.
成功已经避开了专注于阿尔茨海默病(AD)抗A β疗法的试验,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,其越来越被认为是AD发病机制中的关键介质。我们已经使用了体内成像与正电子发射断层扫描(PET),以评估神经胶质细胞的活性,这是破坏AD,其中神经炎症,特别是小胶质细胞,被长期激活,以促进持续的促炎环境。我们的同事已经表明,小胶质细胞诱导星形胶质细胞的A1促炎表型,这是有毒的神经元。我们最近发现了第一个也是唯一的PET成像剂,[11 C]CPPC,它通过与巨噬细胞集落刺激因子-1受体(CSF 1 R)结合而对小胶质细胞具有特异性。尸检研究表明,AD患者的脑CSF 1 R表达高度增加。我们目前的目标是在神经炎症和死后人脑(健康和AD)的非人灵长类动物模型中验证第二代更具商业可行性的CSF 1 R PET显像剂[18 F] JHU 12809。最终,我们将使用这种药物来开发解决AD神经炎症成分的药物。 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测量狒狒大脑中CSF 1 R的可用性和分布(目标1)。在分级方法中,我们将完成[18 F] JHU 12809的临床前研究,包括放射代谢评估和剂量估计计算(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CSF 1 R密度的测定(目标4)。我们已经获得了eIND所需的毒理学研究的独立资金。在完成该项目后,我们将验证一种靶向CSF 1 R的18F标记放射性示踪剂,该示踪剂越来越被认为是大脑内小胶质细胞的特异性标记物,准备应用于AD和迄今为止尚未在人类受试者中直接和非侵入性研究的其他潜在疾病。值得注意的是,[18 F] JHU 12809(拟定研究中的供试品)对CSF 1 R的特异性甚至高于我们最近的先导药物[11 C]CPPC。[18F] JHU 12809较长的物理半衰期将使其能够通过学术和行业合作进行广泛的翻译和传播。

项目成果

期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)

数据更新时间:{{ journalArticles.updateTime }}

{{ item.title }}
{{ item.translation_title }}
  • DOI:
    {{ item.doi }}
  • 发表时间:
    {{ item.publish_year }}
  • 期刊:
  • 影响因子:
    {{ item.factor }}
  • 作者:
    {{ item.authors }}
  • 通讯作者:
    {{ item.author }}

数据更新时间:{{ journalArticles.updateTime }}

{{ item.title }}
  • 作者:
    {{ item.author }}

数据更新时间:{{ monograph.updateTime }}

{{ item.title }}
  • 作者:
    {{ item.author }}

数据更新时间:{{ sciAawards.updateTime }}

{{ item.title }}
  • 作者:
    {{ item.author }}

数据更新时间:{{ conferencePapers.updateTime }}

{{ item.title }}
  • 作者:
    {{ item.author }}

数据更新时间:{{ patent.updateTime }}

Andrew G Horti其他文献

Andrew G Horti的其他文献

{{ item.title }}
{{ item.translation_title }}
  • DOI:
    {{ item.doi }}
  • 发表时间:
    {{ item.publish_year }}
  • 期刊:
  • 影响因子:
    {{ item.factor }}
  • 作者:
    {{ item.authors }}
  • 通讯作者:
    {{ item.author }}

{{ truncateString('Andrew G Horti', 18)}}的其他基金

F-18 labelled PET tracer for imaging macrophage colony stimulating factor 1 receptor (CSF1R) in neuroinflammation
F-18 标记的 PET 示踪剂,用于神经炎症中巨噬细胞集落刺激因子 1 受体 (CSF1R) 的成像
  • 批准号:
    9912886
  • 财政年份:
    2020
  • 资助金额:
    $ 59.67万
  • 项目类别:
F-18 labelled PET tracer for imaging macrophage colony stimulating factor 1 receptor (CSF1R) in neuroinflammation
F-18 标记的 PET 示踪剂,用于神经炎症中巨噬细胞集落刺激因子 1 受体 (CSF1R) 的成像
  • 批准号:
    10260389
  • 财政年份:
    2020
  • 资助金额:
    $ 59.67万
  • 项目类别:
PET Imaging of alpha 7 and alpha4beta2-nAChR in Schizophrenia: Cognitive Relationships
精神分裂症中 α7 和 α4β2-nAChR 的 PET 成像:认知关系
  • 批准号:
    10165041
  • 财政年份:
    2020
  • 资助金额:
    $ 59.67万
  • 项目类别:
PET imaging of soluble epoxide hydrolase (sEH) in human subjects
人体可溶性环氧化物水解酶 (sEH) 的 PET 成像
  • 批准号:
    9916950
  • 财政年份:
    2017
  • 资助金额:
    $ 59.67万
  • 项目类别:
PET imaging of alpha 7 and alpha4beta2-nAChR in schizophrenia: Cognitive Relationships
精神分裂症中 α7 和 α4β2-nAChR 的 PET 成像:认知关系
  • 批准号:
    9762230
  • 财政年份:
    2015
  • 资助金额:
    $ 59.67万
  • 项目类别:
Imaging alpha7-nAChRs in Traumatic Brain Injury
创伤性脑损伤中 α7-nAChR 的成像
  • 批准号:
    8761997
  • 财政年份:
    2014
  • 资助金额:
    $ 59.67万
  • 项目类别:
Extrathalamic nAChR-PET for Imaging Neurodegeneration
丘脑外 nAChR-PET 用于神经退行性疾病成像
  • 批准号:
    8449414
  • 财政年份:
    2011
  • 资助金额:
    $ 59.67万
  • 项目类别:
Extrathalamic nAChR-PET for Imaging Neurodegeneration
丘脑外 nAChR-PET 用于神经退行性疾病成像
  • 批准号:
    8713891
  • 财政年份:
    2011
  • 资助金额:
    $ 59.67万
  • 项目类别:
Extrathalamic nAChR-PET for Imaging Neurodegeneration
丘脑外 nAChR-PET 用于神经退行性疾病成像
  • 批准号:
    8540332
  • 财政年份:
    2011
  • 资助金额:
    $ 59.67万
  • 项目类别:
Extrathalamic nAChR-PET for Imaging Neurodegeneration
丘脑外 nAChR-PET 用于神经退行性疾病成像
  • 批准号:
    8047647
  • 财政年份:
    2011
  • 资助金额:
    $ 59.67万
  • 项目类别:

相似海外基金

Construction of affinity sensors using high-speed oscillation of nanomaterials
利用纳米材料高速振荡构建亲和传感器
  • 批准号:
    23H01982
  • 财政年份:
    2023
  • 资助金额:
    $ 59.67万
  • 项目类别:
    Grant-in-Aid for Scientific Research (B)
Affinity evaluation for development of polymer nanocomposites with high thermal conductivity and interfacial molecular design
高导热率聚合物纳米复合材料开发和界面分子设计的亲和力评估
  • 批准号:
    23KJ0116
  • 财政年份:
    2023
  • 资助金额:
    $ 59.67万
  • 项目类别:
    Grant-in-Aid for JSPS Fellows
Development of High-Affinity and Selective Ligands as a Pharmacological Tool for the Dopamine D4 Receptor (D4R) Subtype Variants
开发高亲和力和选择性配体作为多巴胺 D4 受体 (D4R) 亚型变体的药理学工具
  • 批准号:
    10682794
  • 财政年份:
    2023
  • 资助金额:
    $ 59.67万
  • 项目类别:
Platform for the High Throughput Generation and Validation of Affinity Reagents
用于高通量生成和亲和试剂验证的平台
  • 批准号:
    10598276
  • 财政年份:
    2023
  • 资助金额:
    $ 59.67万
  • 项目类别:
Collaborative Research: DESIGN: Co-creation of affinity groups to facilitate diverse & inclusive ornithological societies
合作研究:设计:共同创建亲和团体以促进多元化
  • 批准号:
    2233343
  • 财政年份:
    2023
  • 资助金额:
    $ 59.67万
  • 项目类别:
    Standard Grant
Collaborative Research: DESIGN: Co-creation of affinity groups to facilitate diverse & inclusive ornithological societies
合作研究:设计:共同创建亲和团体以促进多元化
  • 批准号:
    2233342
  • 财政年份:
    2023
  • 资助金额:
    $ 59.67万
  • 项目类别:
    Standard Grant
Molecular mechanisms underlying high-affinity and isotype switched antibody responses
高亲和力和同种型转换抗体反应的分子机制
  • 批准号:
    479363
  • 财政年份:
    2023
  • 资助金额:
    $ 59.67万
  • 项目类别:
    Operating Grants
Deconstructed T cell antigen recognition: Separation of affinity from bond lifetime
解构 T 细胞抗原识别:亲和力与键寿命的分离
  • 批准号:
    10681989
  • 财政年份:
    2023
  • 资助金额:
    $ 59.67万
  • 项目类别:
CAREER: Engineered Affinity-Based Biomaterials for Harnessing the Stem Cell Secretome
职业:基于亲和力的工程生物材料用于利用干细胞分泌组
  • 批准号:
    2237240
  • 财政年份:
    2023
  • 资助金额:
    $ 59.67万
  • 项目类别:
    Continuing Grant
ADVANCE Partnership: Leveraging Intersectionality and Engineering Affinity groups in Industrial Engineering and Operations Research (LINEAGE)
ADVANCE 合作伙伴关系:利用工业工程和运筹学 (LINEAGE) 领域的交叉性和工程亲和力团体
  • 批准号:
    2305592
  • 财政年份:
    2023
  • 资助金额:
    $ 59.67万
  • 项目类别:
    Continuing Grant
{{ showInfoDetail.title }}

作者:{{ showInfoDetail.author }}

知道了