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: 10689188
• 负责人: LAWRENCE Thomas KIM
• 金额: $ 52.24万
• 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/10689188
• 关键词: Address; Affect; Area; Calcium; Calcium-Sensing Receptors; Cells; Circulation; 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; Membrane; 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; United States; X-Ray Computed Tomography; adenoma; 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; ultrasound

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.

摘要 在美国，每年有10万人患有原发性甲状旁腺功能亢进症(PHPT)。 导致严重发病率的常见疾病。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。目前的技术状态是使用术前成像来定位 异常甲状旁腺，旨在进行一种集中的手术入路，可以限制不必要的 解剖。此外，定位可显示颈部外甲状旁腺的异常位置。 它可以防止徒劳的颈部探查，并指导其他手术方法。尽管取得了进展， 目前的成像技术在检测小腺体方面有几个局限性(特别是在不寻常的位置)。 多发性甲状旁腺异常(15%-20%)。该应用程序建议开发新的 术前能有效检测甲状旁腺的显像剂，术中使用 引导探险。具体地说，我们将构建创新的正电子发射断层扫描(PET)靶向试剂 甲状旁腺特异性标志物和PET/近红外荧光(NIRF)双模式试剂 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新的 放射性氟化、PET探头研制和双模成像的进展。具体地说，钙感应 受体(CSR)是一种C类G蛋白偶联受体，在甲状旁腺和 肾脏。用于成像的CSR特异性药物的开发可能会导致新的PET 对甲状旁腺高度特异的药物(肾脏位于远离我们感兴趣的区域，这将 不干扰PHPT检测)。使用双重示踪剂(光学和PET)不仅会带来高 甲状旁腺检测的灵敏度高，但也便于手术中随后的腺体定位。确实有 这个项目的三个目标。目标1将基于CSR的新配体开发用于甲状旁腺成像的PET试剂。 AIM 2将开发一种强大的放射性氟化方法来产生18F标记的NIRF染料，该染料可以定位在 选择性甲状旁腺。Aim 3将评估我们的先导剂在承载移植人类的啮齿动物模型中的作用 甲状旁腺机能亢进症组织。先导因子将在非人类灵长类动物中得到进一步的表征。 在我们的初步研究中，我们成功地将18F(放射性标记)引入到Cinacalcet(一种小分子)中 靶向CSR)使用光氧化还原放射性氟化。所产生的药剂可以优先被 大鼠甲状旁腺。在非人类灵长类动物中的初步研究也表明，使用18F- 用于甲状旁腺成像的Cinacalcet。在目标2中，我们成功地合成了18F标记的NIRF染料 甲状旁腺和甲状腺靶向。这种方法将通过将PET与 影像引导手术。总而言之，这项多学科研究的首要目标是开发小说 对甲状旁腺高度敏感和特异的显像剂，这将大大有利于 原发性甲状旁腺功能亢进症的处理。