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

描述(申请人提供)：正电子发射断层扫描(PET)是一种高度敏感的、非侵入性的癌症检测方法。虽然这项技术在主要的肿瘤学诊所普遍可用，但其有效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，~(18)F-2-脱氧-D-葡萄糖(2-18F-2-deoxy-D-葡萄糖，FDG)是临床上唯一可用于PET的载体，可被多种肿瘤细胞摄取。然而，FDG的独家使用限制了PET可以成像的癌症类型。已知某些多肽和小蛋白是非常敏感和选择性的癌症靶向剂。然而，用18F标记这些多肽不仅费时费力，而且在临床上不切实际。这一建议通过引入笼状分子来解决这个问题，这种分子能够通过强大的离子、氢键和阴离子-pi类型的相互作用结合氟化物，同时大小不包括竞争阴离子。这些笼子可以附着在上述多肽上，允许立即摄取放射性氟化物，从而产生一种高度简化的标记方案，有可能彻底改变PET在癌症问题上的应用。该方案的具体目标是：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钠水溶液的结合常数。3)将氟结合笼连接到受体特异性的奥曲肽和RGD多肽上。[4]测定CAGE-多肽结合物的血浆稳定性。一旦建立了基本的方法学，这项研究计划的长期目标是首先在小鼠模型中测试[18F CAGE]-多肽结合物，然后最终在研究诊所进行测试。氟结合笼是通过-CH2CH2NRCH2CH2-链连接的1，3，5-环芳烃。广泛的计算模拟表明，这些宿主选择性地与水中的氟化物形成非常稳定的络合物。从市场上可买到的羟乙基三聚氰酸或二乙醇胺出发，提出了两种直接的合成方法。这些笼子可以通过标准的偶联反应连接到生物活性多肽上。标记模式可以是单价(每个笼一肽)或多价(每个笼最多三个肽)。

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).