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.

该副本是使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，这是调查员的机构。 我的实验室重点是开发新的放射性药物和新的MR对比剂，以检测和表征常见的临床状况。有三个主要的努力。 首先，开发针对β细胞相关代谢疾病的早期诊断的非侵入性成像方法，包括1型和2型糖尿病（T1D和T2D），最近从分子成像群落和临床研究者中引起了人们的兴趣。由于胰腺的位置构成的挑战，胰腺内的稀疏β细胞种群以及对疾病发病机理的不良理解，β细胞异常的临床诊断仍然受到限制。这是我们的目标是开发成像剂，不仅针对体内胰腺»细胞，而且还通过功能激活对细胞代谢做出反应。在进行动物实验之前，我们最初将开发一个平台，用于对培养的老鼠和孤立的大鼠胰岛进行高分辨率的MR和PET成像，并使用该技术来筛选氧化氧化还原敏感的宠物剂（64cu -atsm）（64cu -atsm）和氧化还原敏感的paracest剂和基于Cyclen的Tetraamide Agemess（Cyclen基于Cyclen的Tetraamide copplectes of Eu3+或TM3+）。值得注意的是，UT西南医学中心计划购买一种回旋子来促进宠物成像研究和放射性序列的开发。高级成像研究中心（AIRC）几乎完成了建筑，该研究中心将在指定的综合宠物化学实验室的一楼容纳2,000平方英尺的空间。完成后，Sun博士的实验室将占据这个新的空间，并开始与AIRC的体内代谢紧密合作。潜在的高影响力的一个新型项目是给予[1-11c]乙酸盐和[2-11c]乙酸盐，只是试图在TCA循环中相交的体内通量中逗弄体内通量。 其次，转移性癌症中的骨骼病变很常见。该项目的重点是与甲基磷酸或双膦酸酯基序的新型大环骨寻求剂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。最近的药物研究表明，双膦酸盐抗吸附对骨转移的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表面结合，随后被破骨细胞在其中选择性地化为抑制骨的活性。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，如果可以将寻求骨的大环四胺复合物用于多模态化成像骨转移酶的诊断。众所周知，大环螯合剂在动力学上比无环配体更稳定。提出的特定目的如下：1）用甲基磷酸或双膦酸盐或双膦酸盐序列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。 2）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 第三，我们正在研究图像前列腺癌的新方法。该项目的目的是综合和表征为PSMA靶向的纳米偶联物；评估正常和前列腺肿瘤轴承小鼠中纳米偶联物的体内行为；并将纳米偶联物应用于前列腺癌的无创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，开发具有高灵敏度和特异性PCA的新技术具有重要意义。然而，最常用的PET放射性药物18F-FDG，在识别PCA（直到PCA变为转移性之前）并不取得很大的成功，因为它在其他肿瘤中的检测是因为PCA的糖酵解速率较低，并且由于通过尿液的正常极限，PCA的高糖酵解速率高。迄今为止，尚未确定宠物在前列腺癌中的作用。该提案的目的是探索一种新方法，该方法将结合MRI和PET在PCA的诊断成像和分期的优势。我们建议将氧化铁纳米粒子涂上正电子的同位素，以使纳米化的双MRI/PET问题通过多模式（解剖学MRI PLUS功能性PET）分子成像方法检测PCA，以便对PCA诊断的敏感性和特定性进行了显着改善。在此提案中，由于其低端点正电子能量（0.94 meV），我们选择了砷74，该端点正电子能量（0.94 MEV）提供了更高的PET空间分辨率及其相对长的半衰期（17.77天），从而使我们能够执行对偶模态成像探针的过程。从角度来看，漫长的半衰期还允许全球交付此类成像问题。将使用两种靶向分子的前列腺特异性膜抗原（PSMA）（一种新的PSMA单克隆抗体和一种新型的PSMA靶向RNA Apatamer）来构建以PSMA靶向的纳米偶联物。该提案中的三种动物模型（使用两种前列腺癌细胞系C4-2和PC-3细胞）将用于三种动物模型（雌性内，皮下和原位），用于成像探针评估，因为C4-2是一种表达PSMA和PC-3 ISPC-3 ISPSMA-DEVOID AIPCA细胞的雄激素响应细胞，可作为阴性对照。