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

PET 癌症成像肽放射性标记的新方法

• 批准号: 7555042
• 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/7555042
• 关键词: Acids; Address; Anions; Binding; Cancer Detection; Cations; Chemistry; Clinic; Complex; Computer Simulation; Coupling; Deoxyglucose; Diagnostic Imaging; Discipline of Nuclear Medicine; Discrimination; Electrons; Fluoride Ion; Fluorides; Fluorine; Goals; Hydrogen Bonding; Image; 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; Synthesis Chemistry; System; Techniques; Testing; Tracer; Transition Elements; Water; Work; aqueous; base; cancer imaging; cancer type; clinical application; clinical practice; design; diethanolamine; molecular imaging; mouse model; neoplastic cell; novel strategies; oncology; programs; radiotracer; receptor; 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）是一种用于检测癌症的高灵敏度、非侵入性方法。尽管该技术在主要的肿瘤诊所中普遍可用，但其实用性仍然受到放射性标记方法的限制。PET主要使用发射正电子的氟同位素18F。目前，PET中18F临床应用的唯一实际载体是2-18F-2-脱氧-D-葡萄糖（FDG），其被许多类型的肿瘤细胞摄取。然而，FDG的独家使用限制了可以通过PET成像的癌症类型。已知某些肽和小蛋白质是非常敏感和选择性的癌症靶向剂。然而，用18F标记这些肽在临床上是费力且不切实际的。该提议通过引入笼状分子来解决这个问题，所述笼状分子能够通过强有力的离子、氢键和阴离子-π型相互作用的组合来结合氟化物，同时尺寸排除竞争阴离子。这些笼可以连接到上述肽，以允许放射性氟化物的立即摄取，从而导致高度简化的标记方案，其具有彻底改变PET在癌症问题上的应用的潜力。本课题的具体目标是：1）制备一系列高选择性的氟离子结合笼状化合物。2)测定这些络合剂与氟化物水溶液的缔合常数。3)将氟化物结合笼连接至受体特异性奥曲肽和RGD肽。[4)确定笼-肽缀合物的血浆稳定性。]一旦建立了基本方法，该研究计划的长期目标是首先在小鼠模型中测试[18F笼]-肽缀合物，然后最终在研究诊所中测试。氟结合笼是由-CH 2CH 2NRCH 2CH 2-链连接的1，3，5-环番。大量的计算模型表明，这些主体选择性地与水中的氟化物形成非常稳定的复合物。提出了两种直接的合成方法，从市售的羟乙基氰尿酸或二乙醇胺开始。可以使用标准偶联反应将笼连接到生物活性肽。标记模式可以是单价的（每个笼一个肽）或多价的（每个笼最多三个肽）。