DEVELOPMENT OF PET RADIOPHARMACEUTICALS TARGETING GRPR

针对 GRPR 的 PET 放射性药物的开发

• 批准号: 8266454
• 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 2014-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8266454
• 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）：胃泌素释放肽受体（GRPR）在各种人类肿瘤上过度表达，因此已成为检测和治疗这些癌症的成功靶标。铃蟾肽 (BN) 是一种 14 个氨基酸的肽，与 GRPR 具有高亲和力，放射性标记的 BN 类似物已被评估用于表达 GRPR 的癌症的单光子发射计算机断层扫描 (SPECT) 和正电子发射断层扫描 (PET) 成像。我们的实验室是最早评估用于 PET 成像的正电子发射放射性核素放射性标记的 BN 类似物的实验室之一。具体来说，我们使用 BN 的 8 个 C 端氨基酸 (BN(7-14)) 与 1,4,7,10-四氮杂环十二烷-1,4,7,10-四乙酸 (DOTA) 缀合，并用铜进行放射性标记-64（64铜）。我们已经使用各种 64Cu 标记的 DOTA-BN 类似物在携带前列腺癌或乳腺癌异种移植物的小鼠中证明了 GRPR 特异性摄取和 microPET 成像。然而，众所周知，金属螯合物的不稳定性会导致肝脏和肾脏等非靶组织中放射性金属的吸收增加，从而导致对比度降低。特别是，已表明 64Cu 在体内从 DOTA 解离并转螯合为其他蛋白质，导致非靶组织中的高吸收。最近，1,4,7-三氮杂环壬烷-1,4,7-三乙酸 (NOTA) 已与 BN(7-14) 缀合，并直接与 DOTA 缀合的 BN(7-14) 进行比较。 64Cu 标记的 NOTA 缀合物表现出比 DOTA 缀合物更低的肿瘤摄取，但肝脏积累也较低，导致 NOTA 缀合物的肿瘤与肝脏比率更高。因此，本提案将重点开发可与 BN 类似物缀合的新型双功能 NOTA 配体。我们相信，NOTA 缀合的 BN 类似物可以取得显着的改进，因为 64Cu 标记的 NOTA 缀合的 BN 类似物的肿瘤摄取低于 DOTA 缀合的 BN 类似物，并且缀合策略利用了 NOTA 的羧酸酯臂之一，从而减少了协调号。因此，我们假设与已发表的 NOTA 缀合 BN 类似物相比，与 BN 类似物缀合并用 64Cu 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的比率。第二个假设是 68Ga 标记的 NOTA 缀合 BN 类似物将提供表达 GRPR 的肿瘤的高质量 PET 图像。该提案的具体目标是： 1.) 合成双功能 NOTA 衍生物，并将其表征为与 Cu(II) 和 Ga(III) 的配合物； 2.) 形成 NOTA 衍生物的 64Cu 和 68Ga 标记复合物并进行体外评估； 3.) 将NOTA衍生物与BN类似物缀合，用64Cu或68Ga放射性标记它们，并在体外评估它们； 4.) 在携带肿瘤异种移植物的小鼠体内评价放射性标记的BN类似物作为GRPR PET成像的放射性药物。在这项研究结束时，我们预计将开发出用于 GRPR PET 成像的 64Cu 标记 BN 类似物和 68Ga 标记 BN 类似物，这比用于 PET 成像的现有 BN 类似物有显着改进。公共健康相关性：在本研究结束时，我们预计将开发出用于 GRPR PET 成像的 64Cu 标记 BN 类似物和 68Ga 标记 BN 类似物，这比用于 PET 成像的现有 BN 类似物有显着改进。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。

项目成果

In vitro and in vivo evaluation of a 64Cu-labeled NOTA-Bn-SCN-Aoc-bombesin analogue in gastrin-releasing peptide receptor expressing prostate cancer.

64Cu 标记的 NOTA-Bn-SCN-Aoc-铃蟾肽类似物在表达胃泌素释放肽受体的前列腺癌中的体外和体内评估。

• 发表时间: 2012-07
• 影响因子: 3.1
• 作者: Craft, Jeffrey M;De Silva, Ravindra A;Lears, Kimberly A;Andrews, Rebecca;Liang, Kexian;Achilefu, Samuel;Rogers, Buck E
• 通讯作者: Rogers, Buck E

Novel hexadentate and pentadentate chelators for ⁶⁴Cu-based targeted PET imaging.

用于基于 Cu 的靶向 PET 成像的新型六齿和五齿螯合剂。

• 发表时间: 2014-04-15
• 影响因子: 3.5
• 作者: Sin, Inseok;Kang, Chi Soo;Bandara, Nilantha;Sun, Xiang;Zhong, Yongliang;Rogers, Buck E;Chong, Hyun
• 通讯作者: Chong, Hyun

Matched-pair, 86Y/90Y-labeled, bivalent RGD/bombesin antagonist, [RGD-Glu-[DO3A]-6-Ahx-RM2], as a potential theranostic agent for prostate cancer.

匹配对、86Y/90Y 标记、二价 RGD/bombesin 拮抗剂 [RGD-Glu-[DO3A]-6-Ahx-RM2]，作为前列腺癌的潜在治疗诊断剂。

• 发表时间: 2018
• 影响因子: 3.1
• 作者: Bandara, Nilantha;Stott Reynolds, Tamila J;Schehr, Rebecca;Bandari, Rajendra P;Diebolder, Philipp J;Krieger, Stephanie;Xu, Jingli;Miao, Yubin;Rogers, Buck E;Smith, Charles J
• 通讯作者: Smith, Charles J

Copper-64 radiolabeling and biological evaluation of bifunctional chelators for radiopharmaceutical development.

用于放射性药物开发的双功能螯合剂的铜 64 放射性标记和生物学评价。

• 发表时间: 2012-11
• 影响因子: 3.1
• 作者: De Silva RA;Jain S;Lears KA;Chong HS;Kang CS;Sun X;Rogers BE
• 通讯作者: Rogers BE