Optimised Production of Commercial Grade Fluorine-18 Medical Imaging Agents

正电子发射断层扫描（PET）是一种非侵入性医学成像技术，它允许在体内确定标记分子的生物分布和药代动力学。由于这些相对于其他成像方式（如MRI、CT、x射线）的关键优势，全球对PET成像服务的需求显著增加，2007年进行了180万次临床手术（3.32亿美元），比2006年增长了21%。随着PET服务的普及，特别是在美国以外地区，预计到2015年每年将有710万例手术，这种快速增长预计将长期持续下去。然而，目前的建议非常重要的是，这个市场的绝大多数（约95%）目前只涉及单一显像剂的应用；[18F]FDG，它是通用的，因此通常只用于检测肿瘤中代谢活跃的肿瘤。这种令人惊讶的缺乏合适显像剂的直接原因是目前传统合成放射化学方法的局限性，这些局限性严重限制了在单个成像分子中定位氟-18标签，以及实际可有效用作显像剂的分子类别。事实上，在大多数情况下，合成合适的示踪剂需要多个步骤和多个锅转换，但氟-18的半衰期非常短（半衰期= 110分钟），加上所需方法的复杂性，使得过程自动化、临床前到临床研究的转化以及治疗和/或诊断领域的扩展（例如神经病学、内分泌学和心脏病学等）极其困难。为了满足这一迅速增长的需求，纽卡斯尔大学的研究人员开发了第一个通用的、高效的、高选择性的方法来形成[18F]氟芳烃显像剂。该工艺对底物很少或没有限制，从而允许生产以前使用传统合成方法无法获得的多种候选示踪剂。此外，该技术采用“一步一锅”工艺，与主衬底无关。这对于未来的过程自动化和现有的技术匹配是必不可少的，并且从最终阶段GMP级生产的角度来说具有至关重要的意义。例如，4[18F]SFB是一种关键的显像剂，广泛用于临床前研究，用于标记肽和其他生物大分子，但迄今为止，它还没有实现其真正的临床潜力，因为它的生产通常涉及一个费力而复杂的“三步三锅”过程。然而，使用专有方法开发了“一步一锅”生产该制剂的工艺，并为2[18F]SFB和3[18F]SFB衍生物提供了唯一途径，允许进一步改进和优化这些制剂。总之，纽卡斯尔大学开发的技术首次使多种显像剂的高效和低成本制备成为可能，这些显像剂可用于各种诊断和/或治疗应用。临床访问这样的图书馆不仅使个性化医疗的目标更加接近，而且在满足全球临床、学术和工业PET研究人员的要求方面也有相当大的距离。

Positron Emission Tomography (PET) is a non-invasive medical imaging technique which allows the bio-distribution and pharmacokinetics of labelled molecules to be determined in vivo. Due to these key advantages over other imaging modalities (e.g. MRI, CT, X-ray) the global demand for PET imaging services has seen significant increases with 1.8 million clinical procedures ($332M) being conducted in 2007, a 21% rise on 2006. This rapid growth is expected to continue long term, as access to PET services increases generally, and particularly outside the US, with 7.1 million annual procedures predicted by 2015. However, it's highly significant to the current proposal that the vast majority (>95%) of this market currently only involves the application of a single imaging agent; [18F]FDG, which is generic, and as such typically only used to detect metabolically active tumours in oncology.This surprising lack of suitable imaging agents is the direct result of current limitations in conventional synthetic radiochemical methods, which place severe restrictions on both the positioning of a fluorine-18 label within individual imaging molecules, and the classes of molecule that can actually be effectively used as imaging agents. Indeed, in most cases multiple steps and multiple pot transformations are required to synthesise suitable tracers, but the very short half-life of fluorine-18 (half-life = 110 min) coupled to the complexity of the requisite methodology, make process automation, pre-clinical to clinical research translation, and therapeutic and/or diagnostic area expansion (e.g. neurology, endocrinology, and cardiology etc) extremely difficult.To meet this burgeoning need researchers at Newcastle University have developed the first generic, efficient, and highly selective approach to the formation of [18F]fluoroarene imaging agents. The process places little or no restriction on the substrate thereby allowing the production of multiple tracer candidates that have been previously unobtainable using traditional synthetic approaches. Moreover, the technology uses a 'one-step-one-pot' process, irrespective of the primary substrate. This is both essential with a view to future process automation and existing technology-fit , and of critical significance from the perspective of end stage GMP grade manufacture.By way of example, 4[18F]SFB is a key imaging agent widely used in pre-clinical research to label peptides and other bio-macromolecules, but to date, is yet to realise its true clinical potential as its production typically involves a laborious and complex 'three-step-three-pot' process. However, using proprietary methodology a 'one-step-one-pot' process for the production of this agent has been developed, and has also provided the only route to 2[18F]SFB and 3[18F]SFB derivatives, allowing further refinement and optimisation of these agents.In summary the technology developed at Newcastle makes possible for the first time, the highly efficient and cost effective preparation of multiple imaging agents, to be used in a diverse range of diagnostic and/or therapeutic applications. Clinical access to such a library not only brings the goals of personalised medicine that much closer, but also goes a considerable distance towards meeting the requirements of clinical, academic and industrial PET researchers globally.