Novel radiolabeling methods for molecular imaging probes

分子成像（MI）能够在体内可视化生物过程，如代谢途径，酶活性和受体占有率。MI探针需要放射性示踪剂来定位和定量设计用于探测特定生物过程或附着于某些细胞或生物标志物的分子。放射性示踪剂产生的信号可以被伽马相机（单光子发射计算机断层扫描，或SPECT）或正电子发射断层扫描（PET）扫描仪检测到。最广泛使用的SPECT和PET放射性示踪剂是锝-99m和氟-18。这些同位素因其优异的核性质、相对较低的成本、易于生产和广泛的可用性而具有吸引力。不幸的是，目前用99 mTc和18F放射性标记的方法排除了标记许多感兴趣的生物活性分子。它们的短半衰期（分别为6小时和2小时）决定了标记在合成序列的后期进行，标记后的脱保护/纯化最少。基础科学需要扩展合成工具箱并开发新的标记策略以增加MI探针的数量和可用性。从长远来看，我的目标是建立一个研究计划，桥梁合成有机，有机金属和放射化学，癌症生物学和MI领域。第一步是解决合成SPECT和PET探针的紧迫基础科学挑战。在短期内，我们将设计和开发电化学标记方法，99 mTc夹心化学，生物正交化学和自动化反应器，以促进放射性标记和放射合成序列后期生物活性分子的99 mTc标记。受控电位条件下的阳极氧化代表了一种策略，以克服芳族部分和富电子反应中心与18 F的后期放射性标记的反应性挑战。小的配体，如苯基99 mTc-标记的α-型结构将允许标记的大螯合剂中使用的99 mTc放射性药物不能使用。生物正交偶联反应使这些短寿命放射性同位素的抗体成像成为可能，而自动化平台将简化在放射化学实验室中使用的成像剂的获取。 该研究计划的跨学科性质将为学生创造新的机会，并在合成，有机金属，电子和放射化学以及微流体领域的专家之间的合作。本文提出的99 mTc和99 mTc标记方法将在合成化学、药物化学和MI开发领域产生重大和可衡量的影响，超越新的基础知识的创造。该提案中概述的研究将从根本上影响和改善MI药物的获得，例如用于成像感染，炎症和癌症代谢的药物，这些药物迫切需要医学诊断和药物开发。

Molecular imaging (MI) enables in vivo visualization of biologic processes such as metabolic pathways, enzyme activity and receptor occupancy. MI probes require a radiotracer to localize and quantify a molecule designed to probe specific biological processes or attach to certain cells or biomarkers. Radiotracers produce signals that can be detected by a gamma camera (single photon emission computed tomography, or SPECT) or a positron emission tomography (PET) scanner. The most widely available SPECT and PET radiotracers are technetium-99m and fluorine-18. These isotopes are attractive for their excellent nuclear properties, relatively low cost, ease of production and wide availability. Unfortunately, current methods of radiolabeling with 99mTc and 18F preclude labeling many bioactive molecules of interest. Their short half-lives (6 h and 2 h, respectively) dictate that labeling be done late in the synthetic sequence, with minimal post-labeling deprotection / purification. There is an unmet need for basic science to expand the synthetic toolbox and develop new labeling strategies to increase the number and availability of MI probes. In the long-term, I aim to build a research program that bridges the fields of synthetic organic, organometallic, and radiochemistry, cancer biology and MI. The first step is to solve the urgent basic science challenges in synthesizing SPECT and PET probes. In the short-term, we will design and develop electrochemical fluorination methods, 99mTc sandwich chemistry, bioorthogonal chemistry and automated reactors to facilitate radiofluorination and 99mTc labeling of bioactive molecules at the late stage of radiosynthetic sequences. Anodic oxidation under controlled potential conditions represents a strategy to overcome the reactivity challenge of late-stage radiolabeling of aromatic moieties and electron rich reaction centers with 18F. Small ligands such as phenyl groups 99mTc-labeled in a sandwich-type structure would allow labeling where the large chelating agents employed in 99mTc radiopharmaceuticals cannot be used. Bioorthogonal coupling reactions enable antibody imaging with these short-lived radioisotopes, while automated platforms will simplify access to imaging agents for use in a radiochemical laboratory. The interdisciplinary nature of the research program will create new opportunities for students and collaborations between experts in the field of synthetic, organometallic, electro- and radiochemistry, as well as microfluidics. The fluorination and 99mTc labeling methods proposed here would have a substantial and measurable impact in the fields of synthetic chemistry, medicinal chemistry, and MI development, beyond the creation of new fundamental knowledge. The research outlined in this proposal will fundamentally impact and improve access to MI agents, such as those used for imaging infection, inflammation and cancer metabolism, urgently required for medicinal diagnostics and drug development.