DEVELOPMENT OF PET RADIOPHARMACEUTICALS TARGETING GRPR

针对 GRPR 的 PET 放射性药物的开发

• 批准号: 8077958
• 负责人: Buck E. Rogers
• 金额: $ 31.95万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-08-01 至 2013-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8077958
• 关键词: Acids; Affinity; Amino Acids; Binding; Biodistribution; Bombesin; Bombesin Receptor; C-terminal; Carbon; Cells; Charge; Chelating Agents; Clinical; Complex; Copper; Detection; Development; Diagnostic Neoplasm Staging; Future; Gallium; Half-Life; Health; High temperature of physical object; Human; Image; In Vitro; Injection of therapeutic agent; Ions; Kidney; Label; Laboratories; Ligands; Liver; Malignant Neoplasms; Malignant neoplasm of prostate; Metals; Mus; Normal tissue morphology; Peptides; Positron; Positron-Emission Tomography; Proteins; Publishing; Radioimmunoconjugate; Radioisotopes; Radiolabeled; Radionuclide Imaging; Radiopharmaceuticals; Research; Serum; System; Tissues; Tumor Cell Line; Tumor Tissue; Xenograft procedure; absorption; analog; arm; cancer therapy; carboxylate; cyclen; design; divalent metal; hexadecane; improved; in vivo; insight; lipophilicity; malignant breast neoplasm; metabolic abnormality assessment; metal complex; novel; overexpression; radiotracer; single photon emission computed tomography; triazacyclononane; tumor; tumor xenograft; uptake

DESCRIPTION (provided by applicant): The gastrin-releasing peptide receptor (GRPR) is overexpressed on various human tumors and thus has been a successful target for the detection and treatment of these cancers. Bombesin (BN) is a fourteen amino acid peptide that binds with high affinity to GRPR and radiolabeled BN analogs have been evaluated for single photon emission computed tomography (SPECT) and positron emission tomography (PET) imaging of GRPR-expressing cancers. Our laboratory was amongst the first to evaluate BN analogs radiolabeled with positron-emitting radionuclides for imaging by PET. Specifically, we used the eight C-terminal amino acids of BN (BN(7-14)) conjugated to 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA) and radiolabeled with copper-64 (64Cu). We have demonstrated GRPR-specific uptake and microPET imaging in mice bearing either prostate or breast cancer xenografts using various 64Cu-labeled DOTA-BN analogs. However, it is well known that metal chelate instability leads to increased radiometal absorption in non-target tissues such as the liver and kidneys, leading to decreased contrast. In particular, it has been shown that 64Cu dissociates from DOTA in vivo and transchelates to other proteins leading to high absorption in non-target tissues. Recently, 1,4,7-triazacyclononane-1,4,7-triacetic acid (NOTA) have been conjugated to BN(7-14) and compared directly to DOTA conjugated BN(7-14). The 64Cu-labeled NOTA conjugate demonstrated lower tumor uptake than the DOTA conjugate, but also lower liver accumulation leading to higher tumor to liver ratios for the NOTA conjugate. Therefore, this proposal will focus on the development of novel bifunctional NOTA ligands that can be conjugated to BN analogs. We believe that significant improvements in NOTA conjugated BN analogs can be made since the tumor uptake of the 64Cu-labeled NOTA conjugated BN analog was less than the DOTA conjugated BN analog and that the conjugation strategy utilized one of the carboxylate arms of NOTA, reducing the coordination number. Therefore, we hypothesize that novel bifunctional NOTA ligands conjugated to BN analogs and radiolabeled with 64Cu will result in improved tumor uptake and tumor to normal tissue ratios compared to the published NOTA conjugated BN analog. A secondary hypothesis is that 68Ga- labeled NOTA conjugated BN analogs will provide high quality PET images of GRPR expressing tumors. The Specific Aims of the proposal are: 1.) to synthesize bifunctional NOTA derivatives and characterize them as complexes with Cu(II) and Ga(III); 2.) to form the 64Cu- and 68Ga-labeled complexes of the NOTA derivatives and evaluate them in vitro; 3.) to conjugate the NOTA derivatives to BN analogs, radiolabel them with 64Cu or 68Ga, and evaluate them in vitro; 4.) to evaluate the radiolabeled BN analogs in vivo in mice bearing tumor xenografts as radiopharmaceuticals for PET imaging of GRPR. At the conclusion of this research we expect to have developed a 64Cu-labeled BN analog and a 68Ga-labeled BN analog for PET imaging of GRPR that represents a significant improvement over the existing BN analogs that are used for PET imaging. PUBLIC HEALTH RELEVANCE: At the conclusion of this research we expect to have developed a 64Cu-labeled BN analog and a 68Ga-labeled BN analog for PET imaging of GRPR that represents a significant improvement over the existing BN analogs that are used for PET imaging. These analogs should be useful for the clinical detection and staging of cancers that express GRPR.

描述（由申请人提供）：在各种人类肿瘤上过表达胃蛋白释放的肽受体（GRPR），因此已成为检测和治疗这些癌症的成功靶标。 Bombesin（BN）是一种14种氨基酸肽，与GRPR高亲和力结合，已评估了对GRPR表达癌症的单个光子发射计算机断层扫描（SPECT）和正电子发射断层扫描（SPECT）和正电子发射断层扫描（PET）成像的评估。我们的实验室是第一个评估BN类似物的基本核素放射性核素进行射线核素进行成像的BN类似物的实验室之一。具体而言，我们使用了BN的八个C末端氨基酸（BN（7-14）），该氨基酸偶联为1,4,7,10-TetraazacyClododecane-1,4,7,7,7,10-tetraacetic Acid（DOTA），并用copper-64（64CU）进行放射性标记。我们在使用各种64CU标记的DOTA-BN类似物的小鼠中证明了带有前列腺癌或乳腺癌异种移植的小鼠中的GRPR特异性摄取和MicroPET成像。然而，众所周知，金属螯合的不稳定性会导致肝脏和肾脏等非靶向组织中的放射线吸收增加，从而导致对比度下降。特别是，已经表明，64CU从体内DOTA分离，并将其转移至其他蛋白质，从而导致非靶向组织中的高吸收。最近，已将1,4,7-三氮烷烯烷-1,4,7-三乙酸（NOTA）与BN结合（7-14），并直接与DOTA共轭BN进行了比较（7-14）。 64CU标记的Nota结合物比DOTA结合物显示出较低的肿瘤摄取，但肝脏积累较低，导致NOTA结合物的肿瘤与肝比率更高。因此，该提案将集中于可以与BN类似物共轭的新型双功能的Nota配体的发展。我们认为，由于64cu标记的nota nota共轭BN类似物的肿瘤吸收的肿瘤吸收少于DOTA共轭BN类似物，因此可以做出显着改善，并且使用了共轭策略，因此使用了Nota的羧酸酯臂，并降低了均匀的配置数。因此，我们假设与已发表的NOTA共轭BN类似物相比，与BN类似物结合并用64CU进行放射性标记的新型双功能NOTA配体将改善肿瘤摄取和肿瘤与正常组织比率。次要假设是68GA标记的NOTA共轭BN类似物将提供GRPR表达肿瘤的高质量PET图像。该提案的具体目的是：1。）合成双功能的Nota衍生物并将其表征为与Cu（II）和GA（III）的复合物； 2.）形成nota衍生物的64cu和68ga标记的复合物，并在体外评估它们； 3.）要将nota衍生物与BN类似物结合在一起，请使用64CU或68GA将其放射性标记，然后在体外评估它们； 4.）评估带有肿瘤异种移植物作为GRPR PET成像的放射性分析的小鼠中的放射性标记的BN类似物。在这项研究的结论中，我们期望开发一个标记为64cu标记的BN类似物和一个68GA标记的BN类似物，用于GRPR的PET成像，这代表了对用于PET成像的现有BN类似物的显着改善。公共卫生相关性：在这项研究的结论中，我们希望开发出64秒标记的BN类似物和68GA标记的BN类似物，用于GRPR的PET成像，这代表了对用于PET成像的现有BN类似物的显着改善。这些类似物对于表达GRPR的癌症的临床检测和分期应该有用。