Synthesis and evaluation of novel bifunctional chelators based on the DATA chelator scaffold for 68Ga-positron emission tomography

68Ga具有许多特性，许多人认为它非常有希望通过PET/CT在疾病和感染的临床成像中得到更广泛的应用。需要合适的螯合剂来稳定68Ga（III）并促进靶向载体的放射性标记。目前，68Ga螯合的行业现有产品是DOTA衍生物，它在稳定性和放射性标签效率方面定义了标准要求，但存在局限性。临床应用倾向于简单的试剂盒型制备方案，其中将给药前步骤保持在最低限度。为了实现这一设置并实现68Ga的更广泛的临床应用，需要在温和条件下（298 K, pH 4-7）快速（<5分钟）放射性标记而不影响稳定性的螯合剂。我们开发了一种新型螯合剂系列，具有优异的放射性标签和稳定性，符合这些标准。这些特性等于甚至超过了最有前途的螯合剂。该螯合剂同时具有非环和环的特性，代表了一种新的68Ga螯合剂设计方法。宽pH范围和低温的组合是前所未有的，并提供了将68Ga-PET开放给更大范围的载体和准备注入套件型放射性标记方案的潜力。所提出的研究的总体目标是继续发展这些螯合剂作为双功能螯合剂在68Ga-PET中的应用，其中心思想是展示新系统的潜力。为了实现这一目标，我们概述了必要的步骤，每一个步骤都有自己的具体目标。开发的螯合剂不具有以其当前形式共轭到矢量的潜力。最初的目的是在螯合剂上引入偶联基团。在前期工作确定的4种候选螯合剂的基础上，设计了一系列8种螯合剂，初步工作将集中在这些螯合剂的合成和放射化学评价上。在这些调查之后确定的有利候选者将被共轭到目标载体（TV）上。选择了一种经过充分研究的TV （[Tyr3]奥曲肽），以便与目前的实例进行有效的比较。该载体也具有很高的商业和临床价值，并将用于开发试剂盒型放射性标记方案。放射性标签所需的恶劣条件排除了温度和/或pH不稳定电视的应用。螯合剂在非常温和的条件下（pH 4 - 7,298 K）产生放射性标记，因此允许使用不稳定的TVs。如果我们能够证明在这些温和的条件下可以进行电视共轭和随后的放射性标签，那么就可以在68Ga-PET内使用温度和/或pH不稳定的电视。如果成功，这将是68Ga套件型放射性标签的第一个例子，并与非常成功的99mTc模拟进行类比。

68Ga possesses a number of properties which many believe make it a very promising candidate for wider application in clinical imaging of disease and infection via PET/CT. A suitable chelator is required to stabilize the 68Ga(III) and facilitate radiolabeling of a targeting vector. The current industry incumbents for chelation of 68Ga are DOTA derivatives, which define the standard requirements in terms of stability and radiolabeling efficiency, but have limitations. Clinical application favors simple kit-type preparation protocols in which pre-administration steps are kept to a minimum. In order to realize this setup and achieve wider clinical application of 68Ga, chelators are required which radiolabel faster (<5 min) under mild conditions (298 K, pH 4-7) without compromising stability. We have developed a novel chelator series which shows excellent radiolabelling and stability characteristics that fulfill these standards. The characteristics equal and exceed those of the most promising chelators. The chelators possess both acyclic and cyclic character, representing a novel approach to chelator design for 68Ga. The combination of the wide pH range and low temperature at which radiolabelling occurs is unprecedented, and offers the potential to open 68Ga-PET to a wider range of vectors and a ready to inject kit-type radiolabelling protocol. The proposed research has the overall aims to continue the development of these chelators towards application in 68Ga-PET as bifunctional chelators, with the central idea to show the potential of the novel system. In order to carry out this objective we have outlined the necessary steps, each with its own specific objective. The chelators developed do not have the potential to conjugate to a vector in their current form. The initial aim is into introduce coupling groups onto the chelators. A series of 8 chelators has been devised, based on the 4 candidates identified in preliminary work, and initial work will focus on the synthesis and radiochemical evaluation of these chelators. Favorable candidates identified following these investigations will then be conjugated to a targeting vector (TV). A well-studied TV ([Tyr3]octreotide) has been selected so that an effective comparison can be made with the current examples. The vector is also of high commercial and clinical interest and will also be used to develop a kit-type radiolabeling protocol. The harsh conditions required for radiolabeling preclude the application of temperature and/or pH labile TVs. The chelators developed radiolabel under very mild conditions (pH 4 -7, 298 K), and therefore permit the use of labile TVs. If we can show that TV conjugation and subsequent radiolabeling can be conducted under these mild conditions, then it will be possible to utilize temperature and/or pH labile TVs within 68Ga-PET. If successful this will be the first example of kit-type radiolabeling with 68Ga, and an analogy to the highly successful 99mTc analogue.