Electrochemical Synthesis of Radiopharmaceuticals

 描述（由申请人提供）：正电子发射断层扫描（PET）是一种用于癌症研究的分子成像技术，用于观察和测定酶活性、DNA合成、细胞增殖、细胞凋亡、受体占有率和基因表达。尽管合成了多种18F标记的PET探针，但它们的临床翻译经常受到阻碍 由于18F的110分钟半衰期导致的严重合成限制。放射性18F的唯一来源是18F-氟化物阴离子，它只能与带有部分正电荷的分子反应。目前，如果示踪剂结构在标记位点缺乏正电荷，则必须对其进行修饰以产生该电荷，这使得合成复杂并且不适合常规生产。该提案旨在开发一种新的放射合成平台，使18F-氟化物阴离子能够与中性或部分负性分子反应。如果成功， 将为放射性标记现有的具有挑战性的放射性示踪剂开辟新的方法，也将大大扩展PET探针和使用它们进行的测定的产品组合。我们的初步研究表明，儿茶酚放射性标记的电化学电池中的可行性。我们得到了约10%的载体添加的放射化学产率的模型芳族分子后，一个小时的电解。这些实验使用集成到支持放射性氟化物安全处理的自动化平台中的常规电化学电池进行。这些结果开辟了三条平行的研究途径：优化电化学反应并实现比当前亲电方法更高的比活性（约1000倍高）（目标1），开发微流体电化学电池（目标2），以及研究前体结构并生产临床相关实例（目标3）。这些目标中的每一个都有可能大大提高PET探头的生产。目的1提供了一种更简单的放射性标记技术和一种新的无载体添加的放射性标记方法，以前不适合放射性标记的分子。目标2利用最近的发展和我们在微流体和仪器方面的能力，建立一个具有高效电化学放射性的平台。自动化平台技术将促进电化学亲核放射性同位素合成，并通过其 在Aim 3中的应用中，我们将扩大基于亲核取代的临床PET示踪剂的可用性，无论优化或无载体添加的开发。这将提供一种广泛使用的方法，以提供临床相关的探针。新的合成方法将使放射性标记的癌症PET探针与富电子部分，目前无法访问，由于在合成与传统方法的困难。此外，合成的简化将转化为已知和未来PET探针的改进可用性，这将增强疾病诊断和管理。18F-DOPA患者

 DESCRIPTION (provided by applicant): Positron emission tomography (PET) is a molecular imaging technique used in cancer research to visualize and assay enzyme activity, synthesis of DNA, cell proliferation, apoptosis, receptor occupancy and gene expression. Despite the synthesis of a wide variety of 18F labeled PET probes, their clinical translation is often hindered due to severe synthesis limitations, resulting from the 110-minute half-life of 18F. The only practical source of radioactive 18F is 18F-fluoride anion, which can only react with a molecule bearing partial positive charge. Currently, if tracer structures lack a positive charge at the labeling site they must be modified to create this charge, making synthesis complex and not suitable for routine production. This proposal aims to develop a new radiosynthesis platform to enable 18F-fluoride anion to react with neutral or partially negative molecules. If successful this will open new approaches for radiolabeling existing challenging radiotracers and will also dramatically expand the portfolio of PET probes and assays performed with them. Our preliminary studies demonstrate feasibility of catechol radiolabeling in an electrochemical cell. We obtained ~10% carrier-added radiochemical yield of model aromatic molecules after one hour of electrolysis. These experiments were performed using a conventional electrochemical cell integrated into an automated platform supporting safe handling of radioactive fluoride. These results have opened three parallel research avenues: optimization of the electrochemical fluorination reaction and achievement of higher specific activity than current electrophilic methods (~1000 x higher) (Aim 1), development of the microfluidic electrochemical cell (Aim 2), and investigation of the precursor structure and production of a clinically relevant example (Aim 3). Each of these aims individually has the potential to substantially improve PET probe production. Aim 1 provides a simpler radiofluorination technique and a new no-carrier added radiolabeling method for molecules previously not amenable to radiofluorination. Aim 2 takes advantage of recent developments and our capabilities in microfluidics and instrumentation to build a platform with efficient electrochemical radiofluorination. The automated platform technology will facilitate electrochemical nucleophilic radiofluorination synthesis and through its application in Aim 3 we will expand availability of clinical PET tracers based on nucleophilic fluorination, regardless of optimization or no-carrier added development. This will provide a widely accessible method to provide clinically relevant probes such. The new synthetic method will enable the radiolabeling of cancer PET probes with electron-rich moieties, presently not accessible due to difficulties in synthesis with conventional approaches. Moreover, simplification in synthesis will translate to improved availability of known and future PET probes that will enhance disease diagnosis and management. 18F-DOPA to patients