New Methods for the Expedited Synthesis of C11 and F18 PET Tracers

描述（由申请人提供）：用正电子发射同位素18F和11C标记的化合物已经发现了作为正电子发射断层扫描（PET）示踪剂的强大应用。这些分子探针已成为了解正常脑功能和脑紊乱机制不可或缺的工具。由于这些放射性同位素的半衰期很短，如果要保持足够的放射性发射特性以用作显像剂，18F-特别是11c示踪剂的合成和纯化必须以极快的速度进行。因此，PET技术的发展与新的快速合成和纯化方法的发展密切相关。在这个修订后的提案中，我们概述了放射性合成方法的范式转变，重点是开发一类新的活性实体，这些活性实体是由金属阳离子唯一激活的，这些金属阳离子构成了PET制剂合成中最常用的核素盐的一部分（例如K18F和K11CN）。这种新的反应体系被称为亲核试剂辅助离去基团（NALG），有望显著加快显像剂的放射合成并限制副产物的形成。在我们提出的方法中，PET示踪前体共价附着在聚合物载体上，该载体已被修饰以包含新的反应实体（NALG）。在第二步中，将回旋衍生的氟化物或氰化物添加到聚合物中，形成所需的放射性标记示踪剂作为唯一的产品。除了增加反应速率外，这种前所未有的策略还可以避免副产物的形成，并最大限度地减少反应纯化所需的时间。综上所述，这些反应的改进有望为合成比以前可能具有更高特异性活性和更大分子复杂性的成像探针留下更多的时间。我们将利用这种新的NALG聚合物方法首次合成3-氨基丁酸（GABA）受体激动剂[11C]巴氯芬。作为一种众所周知的靶向GABAB的探针，巴氯芬被广泛用于多发性硬化症、图雷特综合征和肌张力障碍的痉挛治疗。通过新的基于聚合物的方法，[11C]巴氯芬（以及相关的类似物，用于更好的脑渗透）的高效无线电合成有望促进未来GABA受体的PET研究，并最终导致改善与这些受体相关的疾病的治疗方法。

DESCRIPTION (provided by applicant): Compounds labeled with positron-emitting isotopes 18F and 11C have found powerful applications as tracers for positron emission tomography (PET). These molecular probes have become indispensable for understanding the mechanisms of both normal brain function and brain disorders. Due to the short half-lives of these radioisotopes, the synthesis and purification of 18F- and especially 11C-tracers must be performed with extreme rapidity if they are to retain sufficient radio-emitting properties to be useful as imaging agents. Thus the growth of the PET technique has been closely tied to the development of new rapid-synthesis and purification methods. In this revised proposal, we outline a paradigm shift in radiosynthesis methodology by focusing on the development of a new class of reactive entities that are uniquely activated by metal cations that form part of the nuclide salts most often used in the synthesis of PET agents (e.g. K18F and K11CN). This new reactive system termed nucleophile assisting leaving group (NALG) is expected to significantly expedite the radiosynthesis of imaging agents and limit side-product formation. In our proposed approach, a PET tracer precursor is covalently attached to a polymer support that has been modified to contain the new reactive entity (the NALG). In a second step, cyclotron-derived fluoride or cyanide are added to the polymer resulting in the formation of the desired radio labeled tracer as the only product. In addition to increased reaction rates, this unprecedented strategy has been designed to avoid byproduct formation and minimize the time required for reaction purification. Taken together, these reaction improvements are expected to leave more time for the synthesis of imaging probes with potentially higher specific activities and greater molecular complexity than previously possible. We will employ this new NALG polymer method in the first synthesis of [11C]baclofen, a 3- amino-butyric acid (GABA) receptor agonist. As a well known probe for targeting GABAB, baclofen is widely- used for the management of spasticity exhibited in multiple sclerosis, Tourette syndrome, and dystonia. Made possible by the new polymer-based method, the efficient radio synthesis of [11C] baclofen (and related analogs for better brain permeation) is expected to facilitate future PET studies of GABA receptors and ultimately lead to improved therapies for diseases related to these receptors.