PET Imaging Agents for Protoporphyrin IX

原卟啉 IX PET 成像剂

• 批准号: 10330484
• 负责人: Mark Myron Goodman
• 金额: $ 21.51万
• 依托单位: EMORY UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-02-01 至 2025-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10330484
• 关键词: 3-Dimensional; Acids; Address; Affinity; Aminolevulinic Acid; Area; Benzodiazepine Receptor; Biological Markers; Brain; Brain Neoplasms; Breast; Calcium Channel; Cell Proliferation; Cells; Cessation of life; Chemicals; Clinical; Clinical Distribution; Colon; Development; Diagnosis; Evaluation; Excision; FDA approved; Fluorescence; Fluorides; Fluorine; Glioblastoma; Glioma; Goals; Half-Life; Heme; Heterogeneity; Histopathology; Image; Image-Guided Surgery; In Vitro; Infiltration; Intracranial Neoplasms; Ions; Label; Ligands; Malignant - descriptor; Malignant Neoplasms; Metabolic; Metabolism; Methods; Mitochondria; Modeling; Molecular; Monitor; Neuraxis; Operative Surgical Procedures; Oral; Organ; Outer Mitochondrial Membrane; Patient-Focused Outcomes; Patients; Peripheral; Porphyrins; Positron-Emission Tomography; Primary Brain Neoplasms; Production; Prognosis; Prostate; Proteins; Radiation; Radioactivity; Radioisotopes; Radiolabeled; Rattus; Rectum; Recurrence; Resistance development; Respiration; Rodent; Specificity; Steroid biosynthesis; Testing; Time; Tissues; Tracer; Transfection; Tumor Subtype; Tumorigenicity; analog; base; brain tissue; brain tumor imaging; cancer type; clinical application; clinical imaging; enantiomer; enzyme pathway; expression vector; fluorodeoxyglucose; fluorodeoxyglucose positron emission tomography; glioma cell line; heme biosynthesis; imaging agent; imaging approach; imaging capabilities; imaging modality; imaging probe; in vivo; individualized medicine; innovation; metabolic imaging; molecular imaging; neoplastic; neoplastic cell; non-invasive imaging; novel; optical imaging; pre-clinical; protoporphyrin IX; radiochemical; receptor density; receptor expression; treatment response; tumor; tumor behavior; tumor progression; uptake

Project Summary Primary brain tumor is a major central nervous system malignancy with 23,800 estimated total new cases in the US in 2017 resulting in 16,700 deaths. High grade glioblastomas (HGG; WHO grades III and IV) in particular carry a dismal prognosis. Glioblastomas are known for their molecular and cellular heterogeneity which contributes to the highly aggressive malignant behaviors of tumor cells, including high proliferation, infiltration and development of resistance to treatment. Therefore, non-invasive imaging approaches that can provide molecular and metabolic information of the glioblastomas are important to characterize a specific tumor for subtype specific and individualized treatments. As a non-invasive clinical imaging modality, positron emission tomography (PET) is capable of molecular and metabolic imaging applications, however, its application in brain tumor is limited. The clinical standard of fluorodeoxyglucose (FDG) PET has low specificity and is not appropriate for brain tumor imaging given the high FDG uptake in normal brain tissue. Currently, there is a significant unmet need in molecular imaging probes for imaging highly heterogeneous and infiltrating gliomas. The overall objective of this exploratory project is to develop a fluorine-18 labeled analog of 5- aminolevulinic acid (5-ALA), which is an FDA approved imaging tracer for intraoperative imaging of gliomas, to provide molecular and metabolic information of the glioma. This innovative new PET imaging capability can be used to characterize a tumor for subtype specific diagnosis and clinical decisions on individualized treatments as well as monitoring the treatment responses. The central hypothesis of this proposal is that a fluorine-18 labeled 5-ALA will enable PET imaging for glioma metabolism and activity on tumorigenicity and cellular proliferation based upon tumor cell metabolizing 5-ALA to produce protoporphyrin IX in highly heterogeneous and infiltrating gliomas. This hypothesis and scientific premise of the project are supported by our preliminary findings that: 1) in vivo pre-clinical PET evaluation of 13N-5-ALA with rats bearing intracranial 9L gliomas demonstrated highly selective uptake of 13N-5-ALA within the tumor, and tumor specific contrast without background; 2) racemic 3-fluoro-5-ALA shows greater substrate reactivity for protoporphyrin IX synthesis in glioma cells than 5-ALA. Thus, our exploratory development of this novel PET tracer for brain tumor imaging will focus on the following specific aims: 1. to synthesize and in vitro characterize R- and S-3-fluoro-5-ALA; 2. to develop radiolabeling methods for the candidate R- and S-3-[18F] fluoro-5-ALA ligands; and 3. to determine whether developed R- and S-3-[18F] fluoro-5-ALA ligand candidates can be selectively taken up in the intracranial tumors in rodent orthotopic models of glioblastomas.

项目概要 原发性脑肿瘤是一种主要的中枢神经系统恶性肿瘤，估计新发病例总数为 23,800 例 2017 年美国发生的病例导致 16,700 人死亡。高级别胶质母细胞瘤（HGG；WHO III 级和 IV 级） 特别是预后不佳。胶质母细胞瘤以其分子和细胞异质性而闻名 这有助于肿瘤细胞的高度侵袭性恶性行为，包括高增殖， 渗透和治疗耐药性的发展。因此，非侵入性成像方法可以 提供胶质母细胞瘤的分子和代谢信息对于表征特定肿瘤很重要 用于亚型特异性和个体化治疗。作为一种非侵入性临床成像方式，正电子 发射断层扫描 (PET) 能够进行分子和代谢成像应用，但是，其 在脑肿瘤中的应用受到限制。氟脱氧葡萄糖（FDG）PET临床标准特异性低 鉴于正常脑组织中 FDG 的摄取量较高，因此不适合脑肿瘤成像。现在， 对高度异质和渗透性成像的分子成像探针的需求尚未得到满足 神经胶质瘤。该探索性项目的总体目标是开发一种氟 18 标记的 5- 类似物 氨基乙酰丙酸 (5-ALA) 是 FDA 批准的用于胶质瘤术中成像的成像示踪剂， 提供神经胶质瘤的分子和代谢信息。这种创新的新型 PET 成像功能可以 用于表征肿瘤的亚型特异性诊断和个体化治疗的临床决策 以及监测治疗反应。该提案的中心假设是氟 18 标记的 5-ALA 将使 PET 成像能够用于胶质瘤代谢以及致瘤性和细胞活性 基于肿瘤细胞代谢 5-ALA 产生高度异质性原卟啉 IX 的增殖 和浸润性神经胶质瘤。这一假设和该项目的科学前提得到了我们初步的支持 研究结果表明：1) 对患有颅内 9L 神经胶质瘤的大鼠进行 13N-5-ALA 的体内临床前 PET 评估 证明了肿瘤内 13N-5-ALA 的高度选择性摄取，并且肿瘤特异性对比没有 背景; 2) 外消旋 3-氟-5-ALA 在原卟啉 IX 合成中显示出更高的底物反应性 胶质瘤细胞优于5-ALA。因此，我们探索性开发了这种用于脑肿瘤成像的新型 PET 示踪剂 将重点关注以下具体目标： 1. 合成和体外表征R-和S-3-氟-5-ALA； 2. 开发候选R-和S-3-[18F]氟-5-ALA配体的放射性标记方法； 3. 确定 开发的 R- 和 S-3-[18F] 氟-5-ALA 配体候选物是否可以在 啮齿动物胶质母细胞瘤原位模型中的颅内肿瘤。