Solid-Phase Platform for the Preparation of Dual-receptor Targeted PET Agents

描述(申请人提供)：随着受体靶向核医学试剂的成功以及新的成像模式和技术的涌入，人们对开发新型双受体靶向PET试剂越来越感兴趣，这种试剂通过多价或针对单个细胞上的两种不同类型的受体具有高亲和力。这个 当两种受体在某些疾病中都过度表达，但每种受体的密度都相对较低时，双受体靶向探针是非常理想的。然而，目前此类探针的制备需要复杂的有机化学、偶联和放射性标记策略，这极大地阻碍了有前景的探针在临床前和/或临床研究中的广泛和常规应用。因此，我们提出了一种新的策略，为临床前和临床研究中双受体靶向PET试剂的结构优化和常规生产提供了一个高效、健壮和潜在的自动化平台。这一多功能平台将利用固相合成能力来制备可以同时靶向两个受体的PET成像探针。该固体合成平台将通过以下方式显著简化合成：1)使用大量过量的反应物进行快速反应；2)通过Staudinger连接和铜(I)催化/无金属点击化学提高连接效率；3)放射性标记和PET试剂从树脂中释放；以及4)完全消除对层析纯化的需要并显著提高比活性，因为只有放射性标记的试剂可以从树脂中释放，并且在最终的PET试剂产品中不存在未标记的分子。利用该平台，可以在短时间内获得具有较高比活性的双受体靶向PET试剂。为了验证合成平台，将制备针对在胰腺癌中过度表达的两种低密度受体-尿激酶型纤溶酶原激活剂受体(UPAR)和CXC趋化因子受体4(CXCR4)-的PET试剂，并在细胞中进行评估。此外，该平台可以很容易地用于制备用于核/光(或核/磁共振)成像等两种模式的多模式显像剂。如果成功，将开发一个可靠和强大的平台，用于快速制备双受体靶向PET试剂。双受体(uPAR和CXCR4)靶向的PET试剂将被制备并在细胞中进行评估。结合双受体靶向策略和快速固相平台的优点，所制备的PET试剂将为实现胰腺癌的准确和选择性成像提供极好的机会。在未来的R01应用中，我们将开发放大和常规生产的自动化，进行结构和反应条件的优化，并对用于胰腺癌早期诊断的双受体靶向PET显像剂进行体内综合评价。

DESCRIPTION (provided by applicant): With the success of receptor-targeted nuclear medicine based agents as well as the influx of new imaging modalities and technologies, there is increasing interest in the development of novel dual-receptor targeted PET agents that have high affinity through multivalency or target two different types of receptors on a single cell. The dual-receptor targeted probes are extremely desirable when both receptors are over-expressed in certain disease but the density of each is relatively low. However, current preparations of such probes require complex organic chemistry, conjugation and radiolabeling strategies, which greatly hinder widespread and routine utilization of promising probes for preclinical and/or clinical studies. Therefore, we are proposing a novel strategy that provides the basis of an efficient, robust and potentially automated platform for the structure optimization and routine production of dual-receptor targeted PET agents for both preclinical and clinical studies. This versatile platform will employ solid-phase synthesis capabilities for preparing PET imaging probes that can target two receptors simultaneously. The solid synthesis platform will significantly facilitate the ease of synthesis by: 1) using a large excess of reactant for fast reactions; 2) increasing the conjugation efficiency via the Staudinger ligation and Cu(I) catalyzed/metal-free click chemistry; 3) radiolabeling and releasing of PET agents from the resins concomitantly; and 4) completely eliminating the need for chromatography purification and significantly increasing specific activity because only radiolabeled agents can be released from the resin and no unlabeled molecule exists in the final PET agent products. By using this platform, dual-receptor targeted PET agents can be obtained in a short time with high specific activity. To validate the synthetic platform, PET agents targeting two low-density receptors that are over-expressed in pancreatic cancer, urokinase plasminogen activator receptor (uPAR) and CXC chemokine receptor 4 (CXCR4), will be prepared and evaluated in cells. In addition, the platform can be easily adapted to prepare multimodal imaging agents for two modalities such as nuclear/optical (or nuclear/magnetic resonance) imaging. If successful, a reliable and robust platform for the rapid preparation of dual-receptor targeted PET agents will be developed. The dual-receptor (uPAR and CXCR4) targeted PET agents will be prepared and evaluated in cells. Combining the advantages offered by dual-receptor targeting strategy and rapid solid-phase platform, the prepared PET agents will provide an excellent opportunity to realize accurate and selective imaging of pancreatic cancer. In a future R01 application, we will develop the automation for scale-up and routine production, perform the structure and reaction conditions optimization, and conduct the comprehensive in vivo evaluation of the dual-receptor targeted PET imaging agents for the early diagnosis of pancreatic cancers.