A New Generation of Bifunctional Bispidine Chelators for Imaging and Therapeutic Applications

双比丁平台是一种非常刚性的四齿配体，具有相对较大的空腔，已经开发了一种模块化合成方法来合成最多具有可变给体集的十齿配体。已经开发了利用生物载体和/或荧光染料对配体进行容易官能化的方法。两种类型的六齿配体和一种大环四齿配体已用于64CuII PET示踪剂及其与生物载体的相应结合物，对于大环示踪剂，另一个花菁基团已准备好用于动物实验。用七、八和非齿双吡啶和111InIII、213BiIII、177LuIII和225AcIII进行了放射成像和治疗的初步实验，研究了LnIII配合物的光物理性质，评价了两种新的双吡啶的MnII选择性，并收集了关于核磁共振造影剂质子弛豫度的初步数据。这个后续项目的目的是深入研究络合和解链机理，以优化针对~(213)BiIII、~(177)LuIII和~(225)AcIII放射性示踪剂的配基体系，目的是在生理条件下高效且相对快速地络合，在生物条件下保持惰性。目前可用的双吡啶体系的性能已经超过了目前的“金标准”，但我们观察到在预平衡状态下相对不稳定的络合物的快速形成，这需要详细了解并尽可能地防止。双吡啶体系的惰性是非常有效的包裹的结果，这需要在结构功和存在过量生物相关金属离子的动力学研究的基础上针对每个示踪剂体系进行优化。此外，我们建议将LnIII系统进一步发展为基于稀土的荧光探针，并优化我们配体独特的MnII选择性，并开发相应的应用，如磁共振造影剂和细胞内光学和结构探针。

The bispidine platform is a very rigid tetradentate ligand with a relatively large cavity, and a modular synthesis has been developed to produce up to decadentate ligands with variable donor sets. Methods have been developed for an easy functionalization of the ligands with biological vectors and/or fluorescence dyes. Two types of hexadentate and a macrocyclic tetradentate ligands have been used for 64CuII PET tracers and the corresponding conjugates with biological vectors and, for the macrocyclic tracer, an additional cyanine group are ready for animal experiments. Preliminary experiments with hepta-, octa- and nonadentate bispidines and 111InIII, 213BiIII, 177LuIII and 225AcIII for radio-imaging and therapy have been performed, photophysical properties of LnIII complexes have been studied and the MnII selectivity of two new bispidines has been evaluated together with the collection of preliminary data on the proton relaxivity in view of MRI contrast agents. The aim of this follow-up project is to thoroughly study complexation and decomplexation mechanisms in order to optimize the ligand systems specifically for 213BiIII, 177LuIII and 225AcIII radiotracers with the aim of efficient and relatively fast complexation at physiological conditions as well as inertness under biological conditions. The currently available bispidine systems already outperform the current “gold standards” but we have observed the fast formation of relatively labile complexes in a pre-equilibrium and this needs to be understood in detail and prevented as far as possible. The inertness of the bispidine systems is a result of very efficient encapsulation and this needs to be optimized for each tracer system on the basis of structural work and kinetic studies in presence of excess of biologically relevant metal ions. In addition, we propose to further develop the LnIII systems towards lanthanide-based fluorescence probes and optimize the unique MnII selectivity of our ligands and develop corresponding applications such as for MRI contrast agents and in-cell optical and structural probes.