Copper Complexes for Cancer Imaging and Therapy

描述(由申请人提供)： 铜-在正电子发射断层扫描成像和癌症靶向放射治疗方面有应用。这项SBIR的目标之一是研究两种新型的64Cu标记的大环膦酸络合物在正常骨骼中的摄取。这项提案的第二个目标是展示铅化合物64CuDO3P((1，4，7，10-tetraazacyclododecane-1，4，7-tri(methanephosphonic酸)作为放射性药物用于正电子发射断层扫描的骨成像和骨转移治疗的潜力。我们的假设是，64Cu标记的含膦酸基的大环化合物将附着在正常骨和骨转移瘤上，成像和治疗将使用相同的试剂完成。这类药物用于骨转移治疗的优点是，相同药物的剂量学将在治疗前用PET进行测定。我们将使用相同的细胞系(B16F10小鼠黑色素瘤细胞)，通过microPET成像在两个骨转移的小鼠模型中评估64Cu-DO3P。治疗研究将在其中一个转移模型中进行，以确定更高剂量的64Cu-DO3P是否会消融骨肿瘤。我们的具体目标如下：L。合成足量(高达1g)的甲磺酸衍生物DO3A-P和双膦酸酰胺衍生物DO3A-BPA。我们将建立DO3P、DO3A-P和DO3A-BPA的高效液相色谱方法，并建立这些配体的铜络合物以建立纯度水平。2.在溶骨性黑色素瘤骨转移模型中进行~(64)Cu-DO3P的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比较，评价Aim 1的64Cu标记络合物的体内稳定性和骨摄取。如果64Cu-DO3A-P或64Cu-DO3A-BPA在骨组织中有更大的摄取和更理想的清除，那么该试剂将在骨转移模型的PET成像研究中进行进一步的研究。4.进行初步实验，比较未标记的铜-DO3P和未络合的DO3P对两种小鼠骨转移模型的治疗效果。

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.