A New Approach to Peptide Radiolabeling for The Imaging of Cancer by PET

PET 癌症成像肽放射性标记新方法

• 批准号: 7385250
• 负责人: Mark Mascal
• 金额: $ 13.68万
• 依托单位: UNIVERSITY OF CALIFORNIA AT DAVIS
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-01-10 至 2009-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7385250
• 关键词: Acids; Address; Anions; Binding; Cancer Detection; Cations; Chemistry; Clinic; Clinical; Complex; Computer Simulation; Coupling; Deoxyglucose; Diagnostic Imaging; Discipline of Nuclear Medicine; Discrimination; Electrons; Fluoride Ion; Fluorides; Fluorine; Goals; Hydrogen Bonding; Image; Invasive; Ions; Isotopes; Label; Link; Literature; Malignant Neoplasms; Methodology; Methods; Modeling; Octreotide; Peptides; Plasma; Positron; Positron-Emission Tomography; Proteins; Protocols documentation; RGD (sequence); Radioactive; Radioisotopes; Radiolabeled; Reaction; Research; Series; Standards of Weights and Measures; Synthesis Chemistry; System; Techniques; Testing; Tracer; Transition Elements; Water; Work; aqueous; base; cancer imaging; cancer type; clinical application; design; diethanolamine; molecular imaging; mouse model; neoplastic cell; novel strategies; oncology; programs; radiotracer; receptor; size; uptake

DESCRIPTION (provided by applicant): Positron emission tomography (PET) is a highly sensitive, noninvasive method for the detection of cancer. Although the technique is generally available in major oncology clinics, its usefulness is nonetheless restricted by limitations in radiolabeling methodology. PET makes predominant use of the positron-emitting fluorine isotope 18F. Currently, the only practical vehicle for clinical application of 18F in PET is 2-18F-2-deoxy-D-glucose (FDG), which is taken up by many types of tumor cells. The exclusive use of FDG however limits the types of cancers which can be imaged by PET. Certain peptides and small proteins are known to be remarkably sensitive and selective cancer targeting agents. However, the labeling of these peptides with 18F is laborious and impractical in the clinic. This proposal addresses this problem by the introduction of cage-like molecules which are able to bind fluoride by a combination of powerful ionic, hydrogen-bonding, and anion-pi type interactions while size excluding competing anions. These cages can be attached to the above-mentioned peptides to allow the immediate uptake of radioactive fluoride, resulting in a highly simplified labeling protocol which has the potential to revolutionize the application of PET to the cancer problem. The specific goals of this proposal are: 1) To prepare a series of highly selective fluoride-binding cage compounds. 2) To determine the association constants of these complexing agents with aqueous fluoride. 3) To attach the fluoride-binding cages to receptor-specific octreotide and RGD peptides. [4) To determine the blood plasma stability of the cage-peptide conjugates.] Once the basic methodology has been established, the longer-term objectives of this research program are to test the [18F cage]-peptide conjugates first in a mouse model, and then eventually in a research clinic. The fluoride-binding cages are 1,3,5-cylophanes linked by -CH2CH2NRCH2CH2- chains. Extensive computational modeling has shown that these hosts selectively form very stable complexes with fluoride in water. Two straightforward synthetic approaches are proposed starting from commercially available hydroxyethylcyanuric acid or diethanolamine. The cages can be attached to bioactive peptides using standard coupling reactions. The labeling mode may be monovalent (one peptide per cage) or multivalent (up to three peptides per cage).

描述（由申请人提供）：正电子发射断层扫描（PET）是一种高度敏感的无创方法，可用于检测癌症。尽管该技术通常在主要的肿瘤诊所可用，但其有用性仍然受放射标记方法的限制限制。 PET主要使用发射正电子的氟同位素18F。当前，在PET中临床应用临床应用的唯一实际载体是2-18F-2-脱氧-D-葡萄糖（FDG），这是由许多类型的肿瘤细胞占用的。但是，FDG的独家使用限制了可以由PET成像的癌症的类型。已知某些肽和小蛋白质非常敏感和选择性癌症靶向剂。但是，在诊所中，这些肽用18F的标记既费力又不切实际。该建议通过引入类似笼子的分子来解决这个问题，这些分子能够通过强大的离子，氢键和阴离子-PI型相互作用的组合结合氟化物，而大小不包括竞争性阴离子。这些笼子可以连接到上述肽上，以立即吸收放射性氟化物，从而产生了高度简化的标记方案，该方案有可能彻底改变PET在癌症问题上的应用。该提案的具体目标是：1）准备一系列高度选择性的氟化物结合笼化合物。 2）确定这些络合剂与氟化水的关联常数。 3）将氟化物结合的笼子连接到受体特异性的奥曲肽和RGD肽上。 [4）确定笼肽缀合物的血浆稳定性。氟化物结合的笼子是由-CH2CH2NRCH2CH2-链连接的1,3,5-曲组。广泛的计算建模表明，这些宿主在水中有选择地形成非常稳定的复合物。提出了两种直接的合成方法，从市售羟基氰尿酸或二乙醇胺开始。可以使用标准耦合反应将笼子连接到生物活性肽上。标记模式可以是单价（每个笼子一个肽）或多价（每个笼子最多三个肽）。