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

描述（由申请人提供）：已发现用正电子发射同位素18 F和11 C标记的化合物作为正电子发射断层扫描（PET）的示踪剂的强大应用。这些分子探针对于理解正常脑功能和脑疾病的机制是不可或缺的。由于这些放射性同位素的半衰期短，如果18F-和特别是11 C-示踪剂要保持足够的放射性发射性质以用作成像剂，则它们的合成和纯化必须极其快速地进行。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，我们概述了放射合成方法的范式转变，重点是开发一类新的反应性实体，这些实体由金属阳离子独特地活化，这些金属阳离子形成PET试剂合成中最常用的核素盐的一部分（例如K18 F和K11 CN）。这种新的反应系统称为亲核辅助离去基团（NALG），预计将显着加快放射性合成的成像剂和限制副产物的形成。在我们提出的方法中，PET示踪剂前体共价连接到已被修改为包含新的反应性实体（NALG）的聚合物支持。在第二步中，将回旋加速器衍生的氟化物或氰化物加入到聚合物中，导致形成所需的放射性标记的示踪剂作为唯一的产物。除了提高反应速率外，这种前所未有的策略还旨在避免副产物的形成，并最大限度地减少反应纯化所需的时间。总的来说，这些反应改进预计将为合成具有潜在更高比活性和更大分子复杂性的成像探针留下更多的时间。我们将采用这种新的NALG聚合物的方法在第一个合成[11 C]巴氯芬，3-氨基丁酸（GABA）受体激动剂。巴氯芬作为一种众所周知的GABAB靶向探针，广泛用于多发性硬化、抽动秽语综合征和肌张力障碍中表现出的痉挛状态的治疗。通过新的基于聚合物的方法，[11 C]巴氯芬（和相关类似物用于更好的脑渗透）的有效放射性合成有望促进未来GABA受体的PET研究，并最终改善与这些受体相关疾病的治疗。

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.