Imaging of Chemokine Receptors

R&D 2项目总结 趋化因子通过它们的同源受体，协调各种免疫系统的迁移和激活。 因此，细胞在构成许多常见疾病的细胞性炎症的发病机制中起着中心作用。 动脉粥样硬化、阿尔茨海默病、各种形式的炎症性肺病和 无数的癌症。因此，人们对阐明各种趋化因子的作用非常感兴趣。 及其受体在人类疾病以及新疗法和成像方法的开发中的作用 针对的是这个系统。目前尚不清楚是广谱疗法还是个别靶向疗法。 应该被雇佣。因此，成像一组关键的趋化因子受体是否也是不确定的 或者，将特定受体作为诊断试剂来确定疾病活动性将是最有用的， 进展或评估药物治疗效率。然而，明确的是，趋化因子受体成像 代理商还不够发达。鉴于人类疾病发病机制的不断演变，至关重要的是 已开发的成像方法广泛适用于人类。 基于我们在合成各种趋化因子受体靶向的血管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种广谱的趋化因子 受体显像剂用病毒炎性巨噬细胞蛋白-II(vMIP-II)测定总 头颈部肿瘤患者趋化因子受体的表达及趋化因子CC受体的定位 2(CCR2)靶向PET放射性示踪剂，使用多肽ECL1 Inverso(ECL1i)。来自这些研究的信息将 指导进一步的放射性示踪剂优化，并评估人类模拟的潜力。为了达到这一目标，我们将 追求以下具体目标： 目的1.翻译广谱趋化因子受体PET放射性示踪剂[64Cu]DOTA-vMIP-II 成像。我们开发了一种基于[64Cu]DOTA-vMIP-II多肽的放射性示踪剂，用于检测多种趋化因子 并已在多种动物疾病模型和体外人体组织中证明了其潜力。在……里面 目标1A，我们将优化我们的放射性示踪细胞结合试验，以筛选潜在的替代放射性示踪剂候选 同时，通过我们的一个协作项目(CPS)在非人类 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 美国食品和药物管理局的探索性研究新药申请(目标1B)。在AIM 1C我们将在头颈部癌症患者中进行[64Cu]DOTA-vMIP-II的首次人评估：1)评估 2)评价其检测趋化因子受体的能力 表情。 目的2.将CCR2靶向放射性示踪剂[64Cu]DOTA-ECL1i翻译成人体显像剂。我们已经准备好了 特异性检测CCR2受体的[64Cu]DOTA-ECL1i多肽示踪剂及其成像敏感性 在疾病和体外人体组织的多种临床前模型中具有特异性。在目标1中，我们优化了我们的 放射性示踪细胞结合分析和我们的CPS将在体内进一步评估[64Cu]DOTA-ECL1i在 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……里面 目标2B和2C我们将执行目标1B和1C中描述的类似任务，以完成第一个人的研究 在头部和癌症患者中评估这种药物的安全性/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有关趋化因子生物学在人类疾病中的作用的新知识。 发病机制，为新的诊断和治疗范例奠定了基础，并最终改善了人类 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.