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.

该子项目是利用该技术的众多研究子项目之一 资源由 NIH/NCRR 资助的中心拨款提供。子项目和 研究者 (PI) 可能已从 NIH 的另一个来源获得主要资金， 因此可以在其他 CRISP 条目中表示。列出的机构是 对于中心来说，它不一定是研究者的机构。 该提案的重点是合成具有亚甲基膦酸酯或双膦酸酯基序的新型大环寻骨剂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使用 99mTc-MDP（亚甲基二磷酸盐）进行。由于缺乏高特异性和敏感性，99mTc-MDP 骨扫描通常需要其他成像方式的辅助，例如放射线照相、MRI、CT、PET 扫描和/或骨髓活检，以进行最终诊断。最近的药理学研究表明，双膦酸盐抗骨转移吸收作用的机制包括两个步骤：双膦酸盐与羟基磷灰石骨矿物表面结合，随后被破骨细胞选择性内化，抑制破骨细胞活性。在该机制的第一步中，双磷酸盐与羟基磷灰石的长期保留限制了 99mTc-MDP 骨扫描用于骨转移早期检测的特异性和敏感性，因为该复合物的体内稳定性有限且 99mTc 的半衰期较短（t1/2 = 6.01 h）。基于双膦酸盐的药理学机制，我们提出这样的假设：如果可以利用寻骨大环四胺复合物进行骨转移的多模态成像诊断，那么骨转移检测的灵敏度和特异性将显着提高。众所周知，大环螯合剂形成的金属配合物比无环配体在动力学上更稳定。 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，而亚甲基膦酸酯部分则用于破骨细胞靶向。 DO3A-BP 是一种混合配体，同时含有双膦酸盐（靶向破骨细胞）和 DOTA（1,4,7,10-四氮杂环十二烷-1,4,7,10-四乙酸），DOTA 是一种用于金属放射性药物和 MRI 造影剂的传统螯合剂。它们与放射性核素的螯合物（64Cu：t1/2 = 12.7 h；和 177Lu：t1/2 = 6.71 d）将为核骨显像剂提供广泛的放射性半衰期，这不仅可以检测/监测骨转移，还可以进行骨异常的机制研究。此外，我们假设这些相同的寻骨螯合剂将与 Gd(III) 形成稳定的复合物，这赋予它们作为磁共振成像 (MRI) 骨造影剂的潜在应用。 这两个目标都将促进体内癌症成像剂的开发，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型成像/姑息/治疗剂。建议具体目标如下： 目的 I. 合成并表征具有亚甲基膦酸酯或双膦酸酯基序的骨寻踪大环螯合剂，并研究它们与 Cu(II)、Lu(III) 和 Gd(III) 的配位化学 该目标的目标是合成和表征骨寻找配体螯合剂（DO1A3P、DO2A2P 和 DO3A-BP），并获得足够量（约 1 g）用于后续研究。将制备、表征所提出的配体与 Cu(II)、Lu(III) 和 Gd(III) 的复合物，并评估其动力学和热力学稳定性。 水溶液。 目标二。制备和评估 64Cu 和 177Lu 标记复合物作为 PET/SPECT 显像剂，专门用于骨转移的检测和原位监测 该目的的目的是建立用于制备骨寻放射药物的放射化学方案，评估其体内稳定性以及组织摄取和清除，并与当前临床骨扫描剂99mTc-MDP相比，评估其作为PET/SPECT骨显像剂的潜在适用性。最有希望的候选者将在小鼠前列腺癌异种移植物的骨内骨转移模型中使用小动物 PET 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。制备和研究冷钆络合物并确定作为骨转移诊断成像的 MRI 骨造影剂的最佳候选者 该目的是检验以下假设：所提出的寻骨螯合剂将与钆形成稳定的复合物，钆也可用作 MRI 骨造影剂。钆化合物将作为 MRI 骨对比剂进行评估，用于在与 Aim II 相同的骨转移模型中对骨转移进行诊断成像。 我们希望找到能够选择性地在骨组织界面提供长时间高对比度增强的候选物，从而帮助骨成像并能够使用 MRI 来研究骨结构随骨转移进展的变化。