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

描述（由申请人提供）：正电子发射断层扫描（PET）是一种高灵敏度、无创的癌症检测方法。虽然这项技术在主要的肿瘤诊所普遍可用，但它的实用性仍然受到放射性标记方法的限制。PET主要使用正电子发射氟同位素18F。目前，18F在PET中临床应用的唯一实际载体是2-18F-2-脱氧-d -葡萄糖（FDG），它被许多类型的肿瘤细胞所吸收。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标记这些肽在临床上是费力和不切实际的。该提案通过引入笼状分子来解决这个问题，笼状分子能够通过强大的离子、氢键和阴离子π型相互作用结合氟化物，同时大小排除竞争阴离子。这些笼可以附着在上述肽上，以便立即吸收放射性氟化物，从而产生高度简化的标记方案，这有可能彻底改变PET在癌症问题上的应用。本课题的具体目标是：1)制备一系列高选择性氟化物结合笼型化合物。2)测定这些络合剂与氟水溶液的缔合常数。3)将氟化物结合笼连接到受体特异性奥曲肽和RGD肽上。[4]测定笼型肽偶联物的血浆稳定性。一旦基本方法确立，该研究项目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进行测试。氟结合笼是由- ch2ch2nrch2ch2 -链连接的1,3,5-环烷。广泛的计算模型表明，这些宿主选择性地与水中的氟化物形成非常稳定的配合物。提出了两种直接的合成方法，从市售羟乙基氰尿酸或二乙醇胺开始。笼可以通过标准的偶联反应附着在生物活性肽上。标记模式可以是单价（每个笼中一个肽）或多价（每个笼中最多三个肽）。

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).