Imaging of Chemokine Receptors

TR&D 2项目摘要 通过它们的同源受体，趋化因子协调各种类型的免疫细胞的迁移和激活。 因此，在细胞炎症的发病机制中起着核心作用，而细胞炎症是一系列常见的 疾病如动脉粥样硬化、阿尔茨海默病、各种形式的炎性肺病和 许多癌症。因此，有强烈的兴趣，澄清各种趋化因子的作用， 及其受体在人类疾病中的作用以及在新的治疗和成像方法的开发中的作用 针对这个系统。目前，尚不清楚是否广谱或个别靶向治疗， 应该被雇用。因此，对一组关键的趋化因子受体进行成像， 或靶向特定受体将最有用地用作确定疾病活性的诊断剂， 或评估药物治疗效果。然而，很明显的是，趋化因子受体成像 代理商不发达。鉴于人类疾病发病机制的不断演变， 所开发的成像方法可广泛应用于人类。 基于我们在合成各种趋化因子受体靶向PET放射性示踪剂方面的专业知识， 损伤，动脉粥样硬化和癌症的应用，我们的目标是首先翻译一个广谱趋化因子， 受体显像剂使用病毒炎性巨噬细胞蛋白-II（vMIP-II），以确定总体 趋化因子受体在头颈部肿瘤患者中的表达，然后聚焦趋化因子CC受体 2（CCR 2）靶向PET放射性示踪剂，使用肽ECL 1 inverso（ECL 1 i）。这些研究的信息将 指导进一步的放射性示踪剂优化并评估人类成像的潜力。为达致这个目标，我们会 追求以下具体目标： 目标1。人广谱趋化因子受体PET放射性示踪剂[64 Cu]DOTA-vMIP-II的研制 显像我们已经开发了一种基于[64 Cu]DOTA-vMIP-II肽的放射性示踪剂来检测多种趋化因子。 受体，并已证明其在多种动物疾病模型和离体人体组织中的潜力。在 目的1A，我们将优化我们的放射性示踪剂细胞结合试验，以筛选潜在的替代放射性示踪剂候选物 同时，通过我们的一个合作项目（CP）在非人类中评估放射性示踪剂性能。 灵长类疾病模型如果成功，我们将执行必要的任务，以获得批准， 美国食品药品监督管理局的探索性研究新药申请（目的1B）。在Aim中 1C我们将在头颈部癌症患者中进行[64 Cu]DOTA-vMIP-II的首次人体评估，以：1）评估 其安全性、生物分布和辐射剂量学; 2）评价其检测趋化因子受体的能力 表情 目标二。转换CCR 2靶向放射性示踪剂[64 Cu] DOTA-ECL 1 i用于人体成像。我们准备了 一种[64 Cu] DOTA-ECL 1 i肽示踪剂，用于特异性检测CCR 2受体，并证明了成像灵敏度 和体外人体组织中的特异性。在目标1A中，我们优化了 放射性示踪剂细胞结合试验，我们的CP将在[64 Cu] DOTA-ECL 1 i中进行进一步的体内评估。 与人体成像相关的临床前动物模型，以进一步指导放射性示踪剂的评估和开发。在 目标2B和2C我们将执行与目标1B和1C所述相似的任务，以完成首次人体研究 在头部和癌症患者中，以评价其安全性/生物分布和性能特征 放射性示踪剂 最终，这些工具将有助于获得关于趋化因子生物学在人类疾病中的作用的新知识 发病机制，为新的诊断和治疗模式奠定基础，并最终改善人类 健康

TR&D 2 Project Summary Via their cognate receptors, chemokines orchestrate the migration and activation of various classes of immune cells and, thus, play a central role in the pathogenesis of cellular inflammation that underlies a host of common diseases such as atherosclerosis, Alzheimer's disease, various forms of inflammatory lung disease and numerous cancers. As a consequence, there is intense interest in clarifying the roles of various chemokines and their receptors in human diseases and in the development of novel therapeutics and imaging approaches directed at this system. Currently, it is unclear whether broad spectrum or individually targeted therapeutics should be employed. Consequently, it is also uncertain whether imaging a panel of key chemokine receptors or targeting a specific receptor would be most useful as a diagnostic agent to determine disease activity, progression or assess drug treatment efficiency. However, what is clear is that the chemokine receptor imaging agents are underdeveloped. Given the constant evolution in human disease pathogenesis, it is critical the imaging methods that are developed are widely applicable in humans. Building upon our expertise in synthesizing various chemokine receptor targeted PET radiotracers for vascular injury, atherosclerosis and cancer applications, our objective is to first translate a broad spectrum chemokine receptor imaging agent using viral inflammatory macrophage protein-II (vMIP-II) to determine the overall expression of chemokine receptors in head and neck cancer patients and then focus a chemokine CC receptor 2 (CCR2) targeted PET radiotracer using a peptide ECL1 inverso (ECL1i). Information from these studies will guide further radiotracer optimization and assess potential for human imaing. To achieve this objective, we will pursue the following Specific Aims: Aim 1. Translate the broad spectrum chemokine receptor PET radiotracer [64Cu]DOTA-vMIP-II for human imaging. We have developed a [64Cu]DOTA-vMIP-II peptide-based radiotracer to detect numerous chemokine receptors and have demonstrated its potential in multiple animal disease models and ex-vivo human tissue. In Aim 1A, we will optimize our radiotracer cell binding assay to screen potentially alternative radiotracer candidates and in parallel, evaluate radiotracer performance by one of our Collaborative Projects (CPs) in a non-human primate model of disease. If successful, we will then perform the necessary tasks to obtain approval for an Exploratory Investigational New Drug Application from the US Food and Drug Administration (Aim 1B). In Aim 1C we will perform a first-in-man evaluation of [64Cu]DOTA-vMIP-II in head and neck cancer patients to: 1) Assess its safety, biodistribution and radiation dosimetry and; 2) To evaluate its ability to detect chemokine receptor expression. Aim 2. Translate the CCR2 targeted radiotracer [64Cu]DOTA-ECL1i for human imaging. We have prepared a [64Cu]DOTA-ECL1i peptide tracer for specific detection of CCR2 receptor and demonstrated imaging sensitivity and specificity in multiple pre-clinical models of disease and ex-vivo human tissue. In Aim 1A we optimize our radiotracer cell binding assay and our CPs will perform further in vivo assessment of [64Cu]DOTA-ECL1i in preclinical animal models relevant to human imaging to further guide radiotracer evaluation and development. In Aims 2B and 2C we will perform similar tasks as described in Aims 1B and 1C to complete a first-in-man study in head and cancer patients to evaluate the safety/ biodistribution and performance characteristics of this radiotracer. Ultimately, these tools would help acquire new knowledge on the role of chemokine biology in human disease pathogenesis, laying the foundation for new diagnostic and treatment paradigms and ultimately, improved human health.