The development of novel PET/NIRF agents for hyperparathyroidism management

用于甲状旁腺功能亢进治疗的新型 PET/NIRF 药物的开发

• 批准号: 10367213
• 负责人: LAWRENCE Thomas KIM
• 金额: $ 50.73万
• 依托单位: UNIV OF NORTH CAROLINA CHAPEL HILL
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-20 至 2025-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10367213
• 关键词: Address; Affect; Area; Blood Circulation; Calcium; Calcium-Sensing Receptors; Cells; Clinical; Data; Detection; Development; Disease; Dissection; Dyes; Ensure; Evaluation; Excision; Fluorescence; Fluorescent Dyes; G-Protein-Coupled Receptors; Gland; Goals; Human; Hydrogen Bonding; Hyperparathyroidism; Image; Image-Guided Surgery; Imaging Techniques; Interdisciplinary Study; Isotopes; Kidney; Label; Lasers; Lead; Ligands; Location; Methods; Modality; Modeling; Morbidity - disease rate; Multiple Abnormalities; Neck; Nodule; Normal tissue morphology; Operative Surgical Procedures; Optics; Parathyroid Adenoma; Parathyroid gland; Patients; Penetration; Persons; Pharmaceutical Preparations; Pharmacologic Substance; Play; Positron-Emission Tomography; Radio; Rattus; Reaction; Research; Rodent Model; Role; Sestamibi Scan; Signal Transduction; Stains; Technology; Thyroid Gland; Tissues; Tracer; Transplantation; Ultrasonography; United States; X-Ray Computed Tomography; adenoma; base; cinacalcet; design; extracellular; fluorescence-guided surgery; fluorophore; imaging agent; imaging modality; improved; innovation; interest; lymph nodes; nonhuman primate; novel; novel imaging technique; prevent; receptor; small molecule; success; targeted agent

Abstract Affecting >100,000 persons each year in the United States, primary hyperparathyroidism (PHPT) is a common disorder that leads to significant morbidity. For PHPT patients, surgically removing the affected parathyroid gland is the only curative option. The current state of the art is to use preoperative imaging to locate abnormal parathyroid glands, aiming to perform a focused surgical approach that can limit unnecessary dissection. In addition, localization can reveal abnormal locations of the parathyroid glands outside the neck which can prevent fruitless neck exploration and guide alternative surgical approaches. Despite the progress, current imaging techniques have several limitations on detecting small glands (especially in unusual locations) and multiple abnormal parathyroids (occurs in 15-20% of cases). This application proposes to develop new imaging agents that can efficiently detect parathyroid glands preoperatively, and be used intraoperatively to guide exploration. In detail, we will construct innovative positron emission tomography (PET) agents targeting markers specific for parathyroid glands, and PET/near-infrared fluorescence (NIRF) dual modality agents that seamlessly integrate parathyroid detection and image-guided surgery. This project is built upon our recent advances on radiofluorination, PET probe development and dual modality imaging. In detail, calcium sensing receptor (CSR) is a Class C G-protein coupled receptor that is highly expressed in the parathyroid gland and the kidneys. The development of CSR-specific pharmaceuticals for imaging could potentially lead to novel PET agents that are highly specific for parathyroid (kidneys are located far away from our area of interest, which will not interfere with PHPT detection). The use of a dual tracer (optical and PET) would not only introduce high sensitivity for parathyroid detection, but also facilitate subsequent gland localization during surgery. There are three aims for this project. Aim 1 will develop PET agents for parathyroid imaging based on novel ligands of CSR. Aim 2 will develop a robust radiofluorination method to generate 18F labeled NIRF dyes that could localize at parathyroid gland selectively. Aim 3 will evaluate our lead agents in rodent model bearing transplanted human hyperparathyroidism tissue. The lead agent will be further characterized in nonhuman primates. In our preliminary study, we have successfully introduced 18F (radio tag) into cinacalcet (a small molecule targeting CSR) using photoredox radiofluorination. The resulting agent could be preferentially taken up by parathyroid gland in rats. Initial study in non-human primate also suggested the great potential of using 18F- cinacalcet for parathyroid imaging. In aim 2, we successfully generated 18F labeled NIRF dyes for specific parathyroid and thyroid gland targeting. This approach would address the clinical need by integrating PET with image-guided surgery. In summary, the overarching goal of this multi-disciplinary research is to develop novel imaging agents that are highly sensitive and specific for parathyroid, which would greatly benefit the management of patients with primary hyperparathyroidism.

抽象的 在美国，原发性甲状旁腺功能亢进症 (PHPT) 每年影响超过 100,000 人 导致显着发病率的常见疾病。对于 PHPT 患者，手术切除受影响的 甲状旁腺是唯一的治疗选择。目前的技术水平是使用术前成像来定位 异常的甲状旁腺，旨在进行有针对性的手术方法，可以限制不必要的 解剖。此外，定位可以揭示颈部以外甲状旁腺的异常位置 这可以防止颈部探查无效并指导替代手术方法。尽管取得了进步， 当前的成像技术在检测小腺体（特别是在不寻常的位置）方面存在一些局限性 以及多种甲状旁腺异常（发生于 15-20% 的病例）。该应用程序建议开发新的 显像剂可以在术前有效检测甲状旁腺，并在术中使用 指导探索。具体来说，我们将构建创新的正电子发射断层扫描（PET）试剂，针对 甲状旁腺特异性标记物，以及 PET/近红外荧光 (NIRF) 双模制剂 无缝集成甲状旁腺检测和图像引导手术。这个项目是建立在我们最近的 放射性氟化、PET 探针开发和双模态成像方面的进展。详细来说，钙传感 受体（CSR）是一种 C 类 G 蛋白偶联受体，在甲状旁腺和甲状腺中高度表达 肾脏。用于成像的 CSR 特异性药物的开发可能会带来新型 PET 对甲状旁腺高度特异性的药物（肾脏远离我们感兴趣的区域，这将 不干扰 PHPT 检测）。使用双示踪剂（光学和 PET）不仅会引入高 甲状旁腺检测的敏感性，而且还有助于手术期间随后的腺体定位。有 该项目的三个目标。目标 1 将开发基于 CSR 新型配体的用于甲状旁腺成像的 PET 试剂。 目标 2 将开发一种强大的放射性氟化方法来生成 18F 标记的 NIRF 染料，该染料可以定位在 选择性地甲状旁腺。目标 3 将评估我们在携带人类移植的啮齿动物模型中的主要药物 甲状旁腺功能亢进组织。主要药物将在非人类灵长类动物中进一步鉴定。 在我们的初步研究中，我们已成功将 18F（无线电标签）引入到西那卡塞（一种小分子药物）中。 使用光氧化还原放射性氟化作用瞄准企业社会责任（CSR）。由此产生的代理可以优先被 大鼠的甲状旁腺。对非人类灵长类动物的初步研究也表明使用 18F- 的巨大潜力 西那卡塞用于甲状旁腺成像。在目标 2 中，我们成功生成了 18F 标记的 NIRF 染料，用于特定的 甲状旁腺和甲状腺靶向。该方法将 PET 与 图像引导手术。总之，这项多学科研究的总体目标是开发新颖的 对甲状旁腺高度敏感和特异性的显像剂，这将极大地有利于 原发性甲状旁腺功能亢进症患者的治疗。