NOVEL AGENTS FOR DETECTING BONE METASTASIS

检测骨转移的新型试剂

• 批准号: 7956998
• 负责人: XIAOFENG SUN
• 金额: $ 0.89万
• 依托单位: UT SOUTHWESTERN MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-01 至 2010-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7956998
• 关键词: Acids; Address; Advanced Development; Animals; Binding; Bone Tissue; Bone marrow biopsy; Cancer Patient; Chelating Agents; Chemistry; Clinical; Complex; Computer Retrieval of Information on Scientific Projects Database; Contrast Media; Detection; Diagnosis; Diagnostic Imaging; Diagnostic radiologic examination; Early Diagnosis; Evaluation; Follow-Up Studies; Funding; Gadolinium; Goals; Grant; Half-Life; Hybrids; Hydroxyapatites; Image; In Situ; Institution; Investigation; Kinetics; Label; Ligands; Magnetic Resonance Imaging; Malignant neoplasm of prostate; Metabolism; Metals; Metastatic Neoplasm to the Bone; Minerals; Modeling; Monitor; Mus; Nuclear; Osteoclasts; PET/CT scan; Positron-Emission Tomography; Preparation; Protocols documentation; Radioactive; Radioisotopes; Radiopharmaceuticals; Research; Research Personnel; Resources; Sensitivity and Specificity; Solutions; Source; Specificity; Structure; Surface; Technetium Tc 99m Medronate; Testing; Therapeutic Agents; Thermodynamics; Tissues; United States National Institutes of Health; Xenograft procedure; aqueous; base; bisphosphonate; bone; bone imaging; cancer imaging; carbene; design; imaging modality; improved; in vivo; metal complex; multimodality; novel; palliative; phosphonate; radiochemical; single photon emission computed tomography; uptake

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. This proposal is focused on the synthesis of novel macrocyclic bone-seeking agents with methylenephosphonate or bisphosphonate motif and their applications to noninvasive imaging of bone metastases. Currently the diagnostic imaging of bone metastases is commonly performed with 99mTc-MDP (methylene bisphosphonate). Due to the lack of high specificity and sensitivity, 99mTc-MDP bone scan is often aided by other imaging modalities, such as radiography, MRI, CT, PET scans, and/or bone marrow biopsy, for a final diagnosis. Recent pharmacological investigations have revealed that the mechanism of bisphosphonate anti-resorption effects on bone metastases involves two steps: bisphosphonates bind to hydroxyapatite bone mineral surface and subsequently are internalized by osteoclasts selectively where they inhibit the osteoclastic activity. The long retention of bisphosphonates with hydroxyapatite in the first step of the mechanism limits the specificity and sensitivity of a 99mTc-MDP bone scan for early detection of bone metastases due to the limited in vivo stability of the complex and the short half-life of 99mTc (t1/2 = 6.01 h). Based upon the pharmacological mechanism of bisphosphonates, we propose to address the hypothesis that the sensitivity and specificity of bone metastasis detection will be significantly improved if bone-seeking macrocyclic tetraamine complexes can be utilized for multimodality imaging diagnosis of bone metastases . It is well-known that macrocyclic chelators form kinetically more stable metal complexes than acyclic ligands. DO1A3P and DO2A2P are designed to form kinetically stable complexes with 177Lu (t1/2 = 6.71 d) and Gd(III) while the methylenephosphonate moieties are for osteoclast-targeting. DO3A-BP is hybrid ligand featuring both bisphosphonate (targeting osteoclasts) and DOTA (1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid), a traditional chelator used in metal radiopharmaceuticals and MRI contrast agents. Their chelates with radionuclides (64Cu: t1/2 = 12.7 h; and 177Lu: t1/2 = 6.71 d) will provide nuclear bone imaging agents with a wide range of radioactive half lives, which enables not only the detection/monitoring of bone metastases but also the mechanistic studies of bone abnormalities. In addition, we hypothesize that these same bone-seeking chelators will form stable complexes with Gd(III), which endows them with potential applications as magnetic resonance imaging (MRI) bone contrast agents as well. Both goals will advance the development of in vivo cancer imaging agents to improve the detection and diagnosis of bone metastases, and potentially provide novel imaging/palliative/therapeutic agents for the treatment and management of cancer patients. The specific aims are proposed as follows: Aim I. To synthesize and characterize bone-seeking macrocyclic chelators with a methylene-phosphonate or bisphosphonate motif and investigate their coordination chemistry with Cu(II), Lu(III), and Gd(III) The goal of this aim is to synthesize and characterize the bone-seeking ligand chelators (DO1A3P, DO2A2P, and DO3A-BP and obtain adequate amounts (~ 1 g) for follow-up studies. The complexes of proposed ligands with Cu(II), Lu(III), and Gd(III) will be prepared, characterized, and evaluated for their kinetic and thermodynamic stability in aqueous solution. Aim II. To prepare and evaluate 64Cu and 177Lu labeled complexes as PET/SPECT imaging agents specifically for the detection and in situ monitoring of bone metastases The objective of this aim is to establish radiochemical protocols for the preparation of the bone-seeking radiopharmaceuticals, evaluate their in vivo stability and tissue uptake and clearance, and assess their potential applicability as PET/SPECT bone imaging agents as compared to 99mTc-MDP, the current clinical bone-scan agent. The most promising candidates will be tested using small animal PET and small animal SPECT in an intra-osseous bone metastasis model of prostate cancer xenografts in mice. Osteoclast-targeting evaluation will be performed to preliminarily evaluate the specificity of our proposed complexes to bone metastases. Aim III. To prepare and investigate cold gadolinium complexes and identify optimal candidates as MRI bone-contrast agents for diagnostic imaging of bone metastases This aim is to test the hypothesis that the proposed bone-seeking chelators will form stable complexes with gadolinium, which can be used as MRI bone contrast agents as well. The gadolinium compounds will be evaluated as MRI bone-contrast agents for diagnostic imaging of bone metastases in the same bone metastasis model as in Aim II. We hope to identify candidates that give prolonged high contrast enhancement selectively at the bone-tissue interface, thus aiding bone imaging and enabling the use of MRI to study changes in bone structure with progression of bone metastases.

该副本是利用众多研究子项目之一 由NIH/NCRR资助的中心赠款提供的资源。子弹和 调查员（PI）可能已经从其他NIH来源获得了主要资金， 因此可以在其他清晰的条目中代表。列出的机构是 对于中心，这不一定是调查员的机构。 该建议的重点是与甲基磷酸或双膦酸酯基序的新型大环骨寻求骨骼的合成及其在骨转移无创成像中的应用。目前，骨转移的诊断成像通常是用99MTC-MDP（甲基双膦酸盐）进行的。由于缺乏高特异性和敏感性，99MTC-MDP骨扫描通常受到其他成像方式（例如放射线照相，MRI，CT，PET扫描和/或骨髓活检）的帮助，以进行最终诊断。最近的药理学研究表明，双膦酸盐抗吸附对骨转移的作用涉及两个步骤：双膦酸盐与羟基磷灰石骨矿物质表面结合，随后通过破骨细胞在其中选择性地将其内化，从而在其中抑制骨质碎裂活性。在机制的第一步中，双膦酸盐的长期保留率限制了99mTC-MDP骨扫描的特异性和灵敏度，用于早期检测骨转移，因为该复合物的体内稳定性有限，而短期寿命短，而半寿命为99mtc（T1/2 = 6.01 H）。基于双膦酸盐的药理机制，我们建议解决以下假设：如果可以将骨转移检测的敏感性和特异性显着改善，如果可以将寻求骨骼的大环四胺复合物用于多态转移诊断的多模态化诊断。众所周知，大环螯合剂比无环配体形成动力学更稳定的金属络合物。 DO1A3P和DO2A2P旨在与177LU（T1/2 = 6.71 D）和GD（III）形成动力学稳定的复合物，而甲基磷酸甲酯部分则用于破骨细胞靶向。 DO3A-BP是杂化配体，具有双膦酸盐（靶向破骨细胞）和DOTA（1,4,7,7,10-tetraazacyClodododecane-1,4,7,10-乙酸），一种用于金属放射性药物和MRI对比的固定剂的传统螯合剂。它们的螯合物用放射性核素（64CU：T1/2 = 12.7 h;和177LU：T1/2 = 6.71 D）将为核骨成像剂提供广泛的放射性半寿命，这不仅可以使骨转移的检测/监测，还可以使骨异常的机械性研究。此外，我们假设这些相同的寻求骨头螯合剂将与GD（III）形成稳定的复合物，这也赋予了它们作为磁共振成像（MRI）骨对比剂的潜在应用。 这两个目标都将促进体内癌症成像剂的发展，以改善骨转移的检测和诊断，并有可能为癌症患者的治疗和管理提供新颖的成像/姑息/姑息/治疗剂。提出的具体目的如下： AIM I.用甲基膦酸酯或双膦酸盐基序合成和表征寻求骨的大环螯合物，并研究其与Cu（II），LU（III）和GD（III）的配位化学化学 此目的的目的是合成和表征寻求骨的配体螯合剂（do1a3p，do2a2p和do3a-bp，并获得足够量（〜1 g）进行后续研究。拟议的配体的复合物与Cu（ii），lu（iii）和gd（iii）和GERTONIC的拟议配体的络合物将为kin和gin threcy and Intery，以及kin的特征，并将其构成，并将其构成，并将其定为特征。水溶液。 目标II。准备和评估64CU和177LU将复合物标记为PET/SPECT成像剂，专门用于检测和原位监测骨转移 此目的的目的是建立放射化学方案，以制备寻求骨骼的放射性药物，评估其体内稳定性和组织的摄取和清除率，并评估其作为99mtc-MDP的PET/SPECT骨成像药物的潜在适用性，目前是当前的临床骨扫描剂。最有希望的候选者将在小鼠的前列腺癌异种移植物的骨内骨转移模型中使用小动物宠物和小动物SPECT进行测试。 将进行破骨细胞靶向评估，以初步评估我们提出的复合物对骨转移的特异性。 目标三。准备和研究冷gadolinium复合物并确定最佳候选物为MRI骨对比剂，用于诊断骨转移的诊断成像 该目的是检验以下假设：拟议的寻求骨螯合剂将与gadolinium形成稳定的复合物，该复合物也可以用作MRI骨对比剂。 Gadolinium化合物将被评估为MRI骨对比剂，用于与AIM II中同一骨转移模型中骨转移的诊断成像。 我们希望确定在骨组织界面有选择地提高延长高对比度增强的候选者，从而有助于骨骼成像并使MRI使用MRI随着骨转移的进展研究骨结构的变化。