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: 10491342
• 负责人: LAWRENCE Thomas KIM
• 金额: $ 50.74万
• 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/10491342
• 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; 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; 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，原发性甲状旁腺功能亢进症（PHPT）每年影响> 100，000人，是一种 导致严重发病的常见疾病。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，旨在进行集中的手术方法，可以限制不必要的 解剖此外，定位可以揭示异常的位置甲状旁腺以外的颈部 其可以防止无效的颈部探查并引导替代的外科手术方法。尽管取得了进展， 目前的成像技术在检测小腺体（特别是在不寻常的位置）上有几个限制。 和多发性异常甲状旁腺（发生在15-20%的病例中）。本申请旨在开发新的 可以在术前有效检测甲状旁腺的成像剂，并在术中用于 引导探索。详细地说，我们将构建创新的正电子发射断层扫描（PET）药物靶向 甲状旁腺特异性标记物和PET/近红外荧光（NIRF）双模态试剂， 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近的 放射成像、PET探头开发和双模态成像的进展。详细地，钙感测 受体（CSR）是C类G蛋白偶联受体，其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导致新型PET 对甲状旁腺具有高度特异性的药物（肾脏远离我们感兴趣的区域， 不干扰PHPT检测）。双示踪剂（光学和PET）的使用不仅会引入高浓度的示踪剂， 这不仅有助于提高甲状旁腺检测的灵敏度，而且有助于随后在手术期间进行腺体定位。有 这个项目的三个目标。目标1将基于CSR的新型配体开发用于甲状旁腺成像的PET药物。 目标2将开发一种稳健的放射性同位素方法来产生18F标记的NIRF染料， 甲状旁腺选择性。目的3：评价我们的先导化合物在荷人移植瘤鼠模型中的作用 甲状旁腺增生组织将在非人灵长类动物中进一步表征先导剂。 在我们的初步研究中，我们成功地将18F（放射性标记）引入到西那卡塞（一种小分子）中， 靶向CSR）。所得试剂可优先被以下物质吸收： 大鼠的甲状旁腺。在非人灵长类动物中的初步研究也表明，使用18F- 西那卡塞用于甲状旁腺成像。在目标2中，我们成功制备了18 F标记的NIRF染料，用于特异性 甲状旁腺和甲状腺靶向。这种方法将通过将PET与 影像引导手术总之，这项多学科研究的首要目标是开发新的 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患者的管理。