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Characterization of an 18F COX-2 PET ligand for in vivo brain imaging

用于体内脑成像的 18F COX-2 PET 配体的表征

基本信息

批准号：
10349436
负责人：
Francesca Zanderigo
金额：
$ 50万
依托单位：
NEW YORK STATE PSYCHIATRIC INSTITUTE DBA RESEARCH FOUNDATION FOR MENTAL HYGIENE, INC
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-02-15 至 2024-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10349436
关键词：
Acute Adult Affinity Age Alzheimer&apos s Disease Alzheimer&apos s disease brain Amines Amyotrophic Lateral Sclerosis Anti-Inflammatory Agents Arthritis Autoradiography Binding Biological Assay Biological Markers Blood Blood - brain barrier anatomy Blood specimen Body Weight Brain Brain Diseases Brain imaging Brain region Cell Line Chemicals Clinical Clinical Research Control Groups Cyclotrons Data Development Diagnosis Disease Disease Progression Disseminated Malignant Neoplasm Dose Early Diagnosis Equilibrium Evaluation FDA approved Female Fluorine Gender Goals Half-Life Harvest Hour Image Imaging Device In Vitro Inflammatory Inflammatory Arthritis Kinetics Label Lead Ligands Light Lipopolysaccharides Major Depressive Disorder Malignant Neoplasms Manuals Measurement Measures Methods Modeling Monitor Monkeys Mus National Institute of Mental Health Neuraxis Non-Steroidal Anti-Inflammatory Agents Outcome Outcome Measure PTGS2 gene Pain Parkinson Disease Pathogenesis Pathology Pathway interactions Pharmaceutical Preparations Pharmacology Physiological Play Positron-Emission Tomography Prevention Procedures Process Property Psychotropic Drugs Quantitative Evaluations Radiolabeled Role Scanning Scheme Schizophrenia Senile Plaques Severities Severity of illness Ships Signal Transduction Site Slide Staging Standardization Stimulus Stroke Structure Testing Therapy Evaluation Time Tracer Translating Translations Traumatic Brain Injury Treatment Efficacy accurate diagnosis allograft rejection base blood-brain barrier permeabilization bone cGMP production celecoxib cost effective cyclooxygenase 2 density experimental study imaging study in vitro Assay in vivo in vivo evaluation inhibitor kinetic model lipophilicity male microPET mouse model nervous system disorder neuroinflammation neuropathology non-invasive monitor novel organ transplant rejection overexpression radiochemical response screening program sex skeletal tool treatment response uptake

项目摘要

Alzheimer’s disease (AD) pathogenesis is associated with early neuroinflammation, which is considered to contribute to disease progression and severity. Therefore, understanding and regulating inflammatory pathways in the central nervous system (CNS) may contribute to prevention or delay of AD. Cyclooxygenase-2 (COX-2) is induced in response to inflammatory stimuli, and its inhibition underlies the therapeutic efficacy of many non- steroidal anti-inflammatory drugs (NSAIDs). COX-2 expression is significantly elevated in brain in AD and this elevation correlates with the severity of brain amyloid plaque pathology. Hence, in vivo and non-invasive monitoring of COX-2 level in the brain can track COX-2 induction during the course of AD and also examine the clinical benefits of COX-2 inhibition in AD. A positron emission tomography (PET) ligand to quantify the level of functional COX-2 in the brain would allow direct measurement of neuroinflammation in AD, and thereby enable disease staging and therapy evaluation. However, there is no such PET ligand is currently available. In order to establish a clinically useful PET tracer for COX-2 imaging in AD brain, we propose to evaluate highly potent [18F]- labeled COX-2 inhibitors due to the advantages associated with the 110-minute half-life. [18F]-labeled tracers allow scanning for longer duration so as to enable equilibrium scanning and facilitate robust kinetic studies leading to accurate quantification of COX-2. Moreover, they can be transported from a synthesis hub to nearby PET centers that lack a cyclotron and aid cost-effective PET studies. We identified MTP, a high affinity COX-2 inhibitor (IC50 = 2.2 nM; Figure 2), possessing an aromatic site for introducing [18F]-label that is less susceptible for defluorination. MTP also has adequate lipophilicity (LogP = 2.7) to passively traverse the blood-brain barrier (BBB). We synthesized [18F]MTP and successfully demonstrated its specific binding in COX-2 positive BxPC-3 cell lines (Figure 3, 112). In vivo PET imaging was performed in mice, induced with lipopolysaccharide (LPS), and obtained a significantly higher binding in the brain compared to control mice, with no visible skeletal uptake (Figure 4, 150). Subsequent in vitro autoradiography of slide-mounted sections of the harvested brain, established specific binding of the tracer in LPS-induced neuroinflammation (Figures 5 & 6). In light of the above supporting evidence demonstrating BBB permeability, higher binding in neuroinflammation, and specific binding to COX-2, [18F]MTP will be further evaluated along with two backup ligands 2 & 3 (Figure 2), using additional PET imaging in mice models of neuroinflammation as well as AD neuropathology (Aims 1 & 2). The most qualified tracer identified will undergo test-retest dynamic PET quantitative evaluations with concomitant arterial blood sampling in male and female anesthetized monkeys to quantify binding as total distribution volume in various brain regions (Aim 3). We believe, the proposed experiments would lead to the selection of a successful [18F]- COX-2 PET tracer, characterized for the transition to clinical studies in AD for early diagnosis, monitoring therapeutic response, and aid development of new medications.

阿尔茨海默病 (AD) 发病机制与早期神经炎症有关，这被认为会导致疾病进展和严重程度。因此，了解和调节中枢神经系统 (CNS) 中的炎症通路可能有助于预防或延缓 AD 的发生。环加氧酶-2 (COX-2) 是响应炎症刺激而诱导的，其抑制是许多非甾体抗炎药 (NSAID) 治疗效果的基础。 AD 患者大脑中 COX-2 的表达显着升高，这种升高与大脑淀粉样斑块病理的严重程度相关。因此，对大脑中 COX-2 水平的体内和非侵入性监测可以跟踪 AD 过程中 COX-2 的诱导，并检查 COX-2 抑制在 AD 中的临床益处。正电子发射断层扫描 (PET) 配体可量化大脑中功能性 COX-2 的水平，从而可以直接测量 AD 中的神经炎症，从而实现疾病分期和治疗评估。然而，目前还没有这样的PET配体可用。为了建立临床上有用的用于 AD 脑中 COX-2 成像的 PET 示踪剂，我们建议评估高效的 [18F] 标记的 COX-2 抑制剂，因为其半衰期为 110 分钟。 [ 18F]标记的示踪剂允许扫描更长的持续时间，从而实现平衡扫描并促进稳健的动力学研究，从而实现 COX-2 的准确定量。此外，它们可以从合成中心运输到附近缺乏回旋加速器的 PET 中心，并有助于经济高效的 PET 研究。我们鉴定出 MTP，一种高亲和力 COX-2 抑制剂（IC50 = 2.2 nM；图 2），具有用于引入不易脱氟的 [18F] 标记的芳香位点。 MTP 还具有足够的亲脂性 (LogP = 2.7)，可以被动穿过血脑屏障 (BBB)。我们合成了 [18F]MTP 并成功证明了其在 COX-2 阳性 BxPC-3 细胞系中的特异性结合（图 3, 112）。在用脂多糖 (LPS) 诱导的小鼠中进行体内 PET 成像，与对照小鼠相比，在大脑中获得了显着更高的结合，且没有可见的骨骼摄取（图 4, 150）。随后对所收获大脑的载玻片切片进行体外放射自显影，确定了示踪剂在 LPS 诱导的神经炎症中的特异性结合（图 5 和 6）。鉴于上述证据表明 BBB 通透性、神经炎症中较高的结合以及与 COX-2 的特异性结合，[18F]MTP 将与两个备用配体 2 和 3 一起进一步评估（图 2），在神经炎症和 AD 神经病理学小鼠模型中使用额外的 PET 成像（目标 1 和 2）。确定的最合格的示踪剂将接受重测动态 PET 定量评估，同时对雄性和雌性麻醉猴子进行动脉血采样，以量化不同大脑区域中总分布体积的结合（目标 3）。我们相信，所提出的实验将导致选择成功的[18F]-COX-2 PET示踪剂，其特征在于过渡到AD临床研究以进行早期诊断、监测治疗反应并帮助开发新药物。