RESPONSIVE MR AND PET AGENTS

反应灵敏的先生和宠物代理人

• 批准号: 8171659
• 负责人: XIAOFENG SUN
• 金额: $ 1.05万
• 依托单位: UT SOUTHWESTERN MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-09-01 至 2011-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8171659
• 关键词: Acetates; Address; Androgens; Animal Experiments; Animal Model; Antigen Targeting; Arsenic; Behavior; Beta Cell; Binding; Bone marrow biopsy; Cancer Etiology; Cells; Cessation of life; Chelating Agents; Chemistry; Citric Acid Cycle; Clinical; Clinical Investigator; Communities; Complex; Computer Retrieval of Information on Scientific Projects Database; Contrast Media; Cyclotrons; Detection; Development; Diagnosis; Diagnostic Imaging; Diagnostic radiologic examination; Disease; Disseminated Malignant Neoplasm; Early Diagnosis; Evaluation; Excretory function; Faculty; Floor; Funding; Glutamate Carboxypeptidase II; Goals; Grant; Half-Life; Housing; Hydroxyapatites; Image; In Situ; Institution; Insulin-Dependent Diabetes Mellitus; Investigation; Isotopes; Label; Laboratories; Lesion; Ligands; Location; Magnetic Resonance Imaging; Malignant neoplasm of prostate; Medical center; Metabolic Diseases; Metabolism; Metastatic Neoplasm to the Bone; Methods; Minerals; Modality; Monitor; Monoclonal Antibodies; Mus; Nanoconjugate; Non-Insulin-Dependent Diabetes Mellitus; Non-Invasive Cancer Detection; Osteoclasts; Oxidation-Reduction; PC3 cell line; PET/CT scan; Pancreas; Pathogenesis; Population; Positron; Positron-Emission Tomography; Procedures; Prostatic Neoplasms; RNA; Radiopharmaceuticals; Rattus; Research; Research Personnel; Resolution; Resources; Role; Sensitivity and Specificity; Source; Staging; Surface; Technetium Tc 99m Medronate; Techniques; Technology; The Sun; United States; United States National Institutes of Health; Urine; Work; aptamer; base; bisphosphonate; bone; bone imaging; cancer diagnosis; carbene; clinical Diagnosis; cyclen; imaging modality; imaging probe; improved; in vivo; interest; iron oxide; islet; men; metal complex; molecular imaging; multimodality; nanoparticle; nanosized; novel; novel strategies; phosphonate; radiotracer; single photon emission computed tomography; square foot; subcutaneous; tumor; type I and type II diabetes

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. My lab focuses on the development of new radiopharmaceuticals and new MR contrast agents to detect and characterize common clinical conditions. There are three major efforts. First, the development of non-invasive imaging methods for early diagnosis of beta cell associated metabolic diseases, including type 1 and type 2 diabetes (T1D and T2D), has recently drawn interest from the molecular imaging community and clinical investigators. Due to the challenges imposed by the location of the pancreas, the sparsely dispersed beta cell population within the pancreas, and the poor understanding of the pathogenesis of the diseases, clinical diagnosis of beta cell abnormalities is still limited. Thus, our goal is to develop imaging agents that not only target the pancreatic ¿-cell in vivo but also respond to ¿-cell metabolism by functional activation. Before moving to animal experiments, we will initially develop a platform for both high resolution MR and PET imaging of cultured rat ¿-cells and isolated rat islets and use this technology to screen for entrapment of redox sensitive PET agents (64Cu-ATSM) and redox sensitive PARACEST agents (cyclen-based tetraamide complexes of Eu3+ or Tm3+) in ¿-cells. It is noteworthy that UT Southwestern Medical Center has planned to purchase a cyclotron to facilitate PET imaging studies and radiotracer developments. Construction is nearly complete on the Advanced Imaging Research Center (AIRC), which will house a 2,000 sq ft space on the first floor designated for a comprehensive PET chemistry laboratory. Once complete, Dr. Sun's laboratory will occupy this new space and begin to work closely with the faculty of the AIRC on in vivo metabolism. A novel project of potentially high impact is to administer [1-11C]acetate and [2-11C]acetate simultaneously in an attempt to tease out in vivo fluxes intersecting in the TCA cycle. Second, bone lesions in metastatic cancer are common. This project 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. The specific aims are proposed as follows: 1) 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). 2) 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 Third, we are investigating new methods to image prostate cancer. The goal of this project is to synthesize and characterize PSMA-targeted nano-conjugates; evaluate in vivo behavior of the nanoconjugates in normal and prostate tumor bearing mice; and apply the nanoconjugates to noninvasive MRI/PET imaging of prostate cancer. In the United States, prostate cancer (PCa) has been consistently the second leading cause of cancer-related deaths of men. Therefore it is of great significance to develop new techniques for the non-invasive detection of PCa with high sensitivity and specificity. However, the most commonly used PET radiopharmaceutical, 18F-FDG, is not quite successful at identifying PCa (until PCa becomes metastatic) as it is in the detection of other tumors because of the low glycolytic rate of PCa and high background due to the normal excretion of 18F-FDG through urine. To date, the role of PET in prostate cancer has not been established. The goal of this proposal is to explore a new approach that will combine the advantages of MRI and PET for the diagnostic imaging and staging of PCa. We propose to dope positron-emitting isotopes to superparamagnetic iron oxide nanoparticle to make nanosized dual MRI/PET probes for the detection of PCa by multi-modality (anatomical MRI plus functional PET) molecular imaging approaches, so that the sensitivity and specificity of PCa diagnosis could be significantly improved. In this proposal, we choose arsenic-74 due to its low endpoint positron energy (0.94 MeV) that provides higher spatial resolution of PET, and its relatively long half-life (17.77 days) that allows us to carry out the procedures of making the dual-modality imaging probes. In perspective, the long half-life also allows global delivery of such imaging probes. Two prostate specific membrane antigen (PSMA) targeting molecules (a new PSMA monoclonal antibody and a novel PSMA-targeting RNA aptamer) will be used to construct the PSMA-targeted nano-conjugates. Three animal models (intra-femoral, subcutaneous, and orthotopic) using two prostate cancer cell lines, C4-2 and PC-3 cells, will be used for the imaging probe evaluations in this proposal, because C4-2 is an androgen responsive cell expressing PSMA and PC-3 is PSMA-devoid AIPCa cell that will serve as negative control.

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。 研究者 (PI) 可能已从 NIH 的另一个来源获得主要资金， 因此可以出现在其他 CRISP 条目中 列出的机构是。 对于中心来说，它不一定是研究者的机构。 我的实验室专注于开发新的放射性药物和新的 MR 造影剂，以检测和表征常见的临床状况，主要致力于三项工作。 首先，由于面临的挑战，用于早期诊断β细胞相关代谢疾病（包括1型和2型糖尿病（T1D和T2D））的非侵入性成像方法的开发最近引起了分子成像界和临床研究人员的兴趣。由于胰腺的位置、胰腺内β细胞群分布稀疏以及对疾病发病机制的了解不足，β细胞异常的临床诊断仍然受到限制。因此，我们的目标是开发不存在这种情况的显像剂。仅有的瞄准胰腺- 体内细胞也对 ¿ -通过功能激活进行细胞代谢。在进行动物实验之前，我们将首先开发一个用于培养大鼠高分辨率 MR 和 PET 成像的平台 ¿ -细胞和分离的大鼠胰岛，并使用该技术筛选 ¿值得注意的是，德克萨斯大学西南医学中心计划购买一台回旋加速器，以促进 PET 成像研究和放射性示踪剂的开发，先进成像研究中心 (AIRC) 的建设已接近完成，该中心将拥有 2,000 平方英尺的空间。一楼指定为综合 PET 化学实验室。一旦建成，孙博士的实验室将占据这个新空间，并开始与 AIRC 的教师密切合作，研究一个具有潜在高影响力的新项目。是同时给予[1-11C]乙酸盐和[2-11C]乙酸盐，试图梳理出TCA循环中交叉的体内通量。 其次，转移性癌症中的骨病变很常见。该项目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，及其在骨转移的无创成像中的应用。 99mTc-MDP（亚甲基二磷酸盐）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涉及两个步骤：双膦酸盐与羟基磷灰石骨矿物质结合。表面，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，双膦酸盐与羟基磷灰石的长期保留限制了破骨细胞的作用。由于复合物的体内稳定性有限且 99mTc 的半衰期较短（t1/2 = 6.01 h），因此 99mTc-MDP 骨扫描用于早期检测骨转移的特异性和敏感性基于双膦酸盐的药理学机制。 ，我们提出了这样的假设：如果寻骨大环四胺复合物可用于多模态成像诊断，骨转移检测的灵敏度和特异性将显着提高众所周知，大环螯合剂形成比无环配体动力学更稳定的金属配合物，具体目标如下：1）合成和表征具有亚甲基膦酸酯或二膦酸酯基序的骨寻找大环螯合剂。研究它们与 Cu(II)、Lu(III) 和 Gd(III) 的配位化学 2) 制备并评估 64Cu 和 177Lu 标记配合物。专门用于骨转移检测和原位监测的 PET/SPECT 显像剂 第三，我们正在研究前列腺癌成像的新方法，该项目的目标是合成和表征 PSMA 靶向纳米缀合物；评估纳米缀合物在正常和前列腺肿瘤小鼠中的体内行为；并将纳米缀合物应用于非侵入性治疗。前列腺癌的MRI/PET成像在美国，前列腺癌（PCa）一直是男性癌症相关死亡的第二大原因，因此开发前列腺癌的无创检测新技术具有重要意义。 PCa 具有高灵敏度和然而，最常用的 PET 放射性药物 18F-FDG 在识别 PCa 方面并不十分成功（直到 PCa 发生转移），因为它在检测其他肿瘤方面不太成功，因为 PCa 的糖酵解率较低且背景较高。 18F-FDG 通过尿液正常排泄 迄今为止，PET 在前列腺癌中的作用尚未确定，该提案的目标是探索一种结合 18F-FDG 优点的新方法。用于 PCa 诊断成像和分期的 MRI 和 PET 我们建议将正电子发射同位素掺杂到超顺磁性氧化铁纳米颗粒中，制成纳米级双 MRI/PET 探针，用于通过多模态（解剖 MRI 加功能 PET）分子检测 PCa。成像方法，从而可以显着提高 PCa 诊断的敏感性和特异性。在本方案中，我们选择砷 74，因为它的终点正电子能量较低。 （0.94 MeV）提供了 PET 更高的空间分辨率，其相对较长的半衰期（17.77 天）使我们能够进行双模态成像探针的制作过程。两种前列腺特异性膜抗原（PSMA）靶向分子（一种新的 PSMA 单克隆抗体和一种新型 PSMA 靶向 RNA 适体）将用于构建 PSMA 靶向的成像探针。使用两种前列腺癌细胞系 C4-2 和 PC-3 细胞的三种动物模型（股骨内、皮下和原位）将用于本提案中的成像探针评估，因为 C4-2 是表达 PSMA 和 PC-3 的雄激素应答细胞是缺乏 PSMA 的 AIPCa 细胞，将用作阴性对照。