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

bispidine平台是具有相对大的空腔的非常刚性的四齿配体，并且已经开发了模块化合成以产生具有可变供体组的多达十齿配体。已经开发了用生物载体和/或荧光染料容易地官能化配体的方法。两种类型的六齿和一个大环四齿配体已被用于64 CuII PET示踪剂和相应的共轭物与生物载体和大环示踪剂，一个额外的花青基团准备用于动物实验。初步实验与七，八，九齿bispidines和111铟III，213铋III，177 LuIII和225 Ac III的放射性成像和治疗已进行，已研究的LnIII复合物的物理性质和MnII的选择性的两个新的bispidines已被评估与收集的初步数据质子弛豫鉴于MRI造影剂。该后续项目的目的是彻底研究络合和解络合机制，以优化专门用于213 BiIII，177 LuIII和225 AcIII放射性示踪剂的配体系统，目的是在生理条件下有效和相对快速的络合以及在生物条件下的惰性。目前可用的bispidine系统已经优于目前的“金标准”，但我们已经观察到在预平衡中快速形成相对不稳定的复合物，这需要详细了解并尽可能防止。bispidine系统的惰性是非常有效的包封的结果，这需要在过量的生物相关金属离子存在下，基于结构工作和动力学研究，对每种示踪剂系统进行优化。此外，我们建议进一步开发镧系元素为基础的荧光探针的Ln III系统，优化我们的配体的独特MnII选择性，并开发相应的应用，如MRI造影剂和细胞内的光学和结构探针。

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.