Copper Complexes for Cancer Imaging and Therapy

用于癌症成像和治疗的铜配合物

• 批准号: 6687219
• 负责人: MARK WOODS
• 金额: $ 15.96万
• 依托单位: MACROCYCLICS, INC.
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-09-20 至 2005-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6687219
• 关键词: bioimaging /biomedical imaging; biological transport; bone imaging /visualization /scanning; bone neoplasms; chemical synthesis; copper; cyclic compound; disease /disorder model; drug discovery /isolation; high performance liquid chromatography; laboratory mouse; lead; melanoma; metal complex; metastasis; method development; neoplasm /cancer radiation therapy; neoplastic process; nonhuman therapy evaluation; phosphonate; positron emission tomography; radiation dosage; radiopharmacology; skeletal neoplasm

DESCRIPTION (provided by applicant): Copper-64 has applications for positron emission tomography (PET) imaging and targeted radiotherapy of cancer. One of the goals of this SBIR is to study two novel 64Cu-labeled phosphonate macrocyclic complexes for their uptake in normal bone. A second goal of this proposal is to demonstrate the potential of the lead compound, 64Cu-DO3P (1,4,7,10-tetraazacyclododecane-1,4,7-tri(methanephosphonic acid)), as a radiopharmaceutical for bone imaging using positron emission tomography (PET) and therapy for bone metastases. Our hypothesis is that 64Cu-labeled macrocyclic complexes containing phosphonate groups will adhere to normal bone and bone metastases and imaging and therapy will be accomplished with the same agent. The advantage of this class of agents for bone metastasis therapy is that dosimetry with the same agent will be determined with PET prior to therapy. We will evaluate, by microPET imaging, 64Cu-DO3P in two mouse models of bone metastases using the same cell line (B 16F10 mouse melanoma tumor cells). Therapeutic studies will be performed in one of the metastasis models to determine if higher doses of 64Cu-DO3P will ablate the bone tumors. Our Specific Aims are as follows: l. To synthesize sufficient amounts (up to 1g) of the methanephosponate derivative DO3A-P and the bisphosphonate amide derivative DO3A-BPA. We will develop an HPLC method for DO3P, DO3A-P and DO3A-BPA, and the copper complexes of these ligands to establish purity levels. 2. To perform microPET imaging studies on 64Cu-DO3P in an osteolytic melanoma bone metastasis model to see the progression of tumors to the skeleton over the course of tumor growth. 3. To evaluate 64Cu-labeled complexes from Aim 1 for their in vivo stability and bone uptake compared to the lead compound, 64Cu-DO3P. If either 64Cu-DO3A-P or 64Cu-DO3A-BPA has greater uptake in bone and more optimal clearance than 64Cu-DO3P, then that agent will undergo further investigation in PET imaging studies in the bone metastasis model. 4. To perform preliminary experiments to investigate if 64Cu-DO3P, or the most optimal 64Cu complex determined from Aim 3, has therapeutic efficacy in two mouse bone metastasis model compared to unlabeled Cu-DO3P and uncomplexed DO3P.

描述（由申请人提供）： Copper-64 可用于正电子发射断层扫描 (PET) 成像和癌症靶向放射治疗。该 SBIR 的目标之一是研究两种新型 64Cu 标记的膦酸酯大环配合物在正常骨中的吸收。该提案的第二个目标是证明先导化合物 64Cu-DO3P（1,4,7,10-四氮杂环十二烷-1,4,7-三（甲膦酸））作为骨成像放射性药物的潜力正电子发射断层扫描（PET）和骨转移治疗。我们的假设是，含有膦酸基团的 64Cu 标记的大环复合物将粘附在正常骨和骨转移瘤上，并且可以使用相同的试剂完成成像和治疗。此类药物用于骨转移治疗的优点是，使用相同药物的剂量测定将在治疗前通过 PET 确定。我们将通过 microPET 成像，使用相同的细胞系（B 16F10 小鼠黑色素瘤细胞）在两种小鼠骨转移模型中评估 64Cu-DO3P。将在其中一种转移模型中进行治疗研究，以确定较高剂量的 64Cu-DO3P 是否会消融骨肿瘤。我们的具体目标如下： l．合成足够量（最多1g）的甲膦酸酯衍生物DO3A-P和双膦酸酯酰胺衍生物DO3A-BPA。我们将开发一种用于 DO3P、DO3A-P 和 DO3A-BPA 以及这些配体的铜络合物的 HPLC 方法，以确定纯度水平。 2. 在溶骨性黑色素瘤骨转移模型中对 64Cu-DO3P 进行 microPET 成像研究，以观察肿瘤在肿瘤生长过程中向骨骼的进展。 3. 与先导化合物 64Cu-DO3P 相比，评估目标 1 中的 64Cu 标记复合物的体内稳定性和骨吸收。如果 64Cu-DO3A-P 或 64Cu-DO3A-BPA 比 64Cu-DO3P 具有更高的骨吸收和更佳的清除率，则该药物将在骨转移模型的 PET 成像研究中接受进一步研究。 4. 进行初步实验以研究 64Cu-DO3P 或目标 3 确定的最佳 64Cu 复合物与未标记的 Cu-DO3P 和未复合的 DO3P 相比，在两种小鼠骨转移模型中是否具有治疗功效。