Evaluation and application of a novel radioisotope for immuno-PET:Niobium-90

在过去的几十年里，全球肿瘤病例的每年增加刺激了核医学在癌症诊断和治疗方面的快速发展。一种新的诊断选择的一个吸引人的例子是免疫-PET：用高分辨率和高灵敏度的正电子发射断层扫描(PET)跟踪和定量标记的蛋白质，如单抗(MAb)。常见的正电子发射体如F-18(T1=110min)、O-15(T2=2.04min)、N-13(T1=9.96min)和C-11(T2=20.4min)对免疫-PET几乎毫无用处，因为蛋白质的药代动力学和药效学需要几个小时到几天，而且这些放射性同位素的物理半衰期太短。这一事实要求开发具有合适特性(物理半衰期、衰变模式)的新的放射性同位素来识别放射性标记蛋白。本项目旨在评价Nb-90作为免疫-PET的同位素。它的中间半衰期为14.6小时，高正电子分支(53%)使其适合于抗体和抗体片段的体内定量成像。在以前的研究中，我们展示了制备NB-90标记抗体的初步策略及其体外高稳定性。本项目的目的是：a)为了改进放射性核素的生产方法，b.为了优化其放化分离，c.)研究合适的标记方案，以及d.)标记选定的单抗。E.)最后，对NB-90标记生物分子的体内评价进行了计划。我们将评估全长抗体以及抗体片段的体内行为。以三种成熟的PET同位素为参照物，分别是长药代动力学过程的Zr-(T1=78.4h)和抗体片段的Ga-68(t1/2=67.7min)和Sc-44(t1/2=3.92h)。为了将同位素连接到生物分子上，相同的双功能螯合剂去铁胺被认为是首选的配体。

A yearly increase in tumor cases worldwide stimulated a fast progression of nuclear medicine in the last decades in the diagnosis and treatment of cancer. One attractive example of a novel diagnosis option is immuno-PET: the tracking and quantification of labeled proteins such as monoclonal antibodies (mAb) with positron emission tomography (PET) at high resolution and sensitivity. Common positron emitters as F-18 (T½ = 110 min), O-15 (T½ = 2.04 min), N-13 (T½ = 9.96 min) and C-11 (T½ = 20.4 min) are practically useless for immuno-PET, because the pharmacokinetics and pharmacodynamics of proteins take from several hours to several days and the physical half-lives of these radioisotopes is too short. This fact calls for the development of new radioisotopes with appropriate characteristics (physical half-life, decay mode) to radiolabel proteins.This project aims to evaluate Nb-90 as an isotope for immuno-PET. Its intermediate half-life of 14.6 hours and the high positron branching (53 %) make it appropriate for quantitative in vivo imaging of antibodies and antibody fragments. In previous studies we showed initial strategies for the preparation of Nb-90-labeled antibodies and their high in vitro stability.The aims of this project are:a.) to improve the production method of the radionuclide,b.) to optimize its radiochemical separation, c.) to investigate appropriate labeling protocols, andd.) to label selected monoclonal antibodies.e.) Finally, the in vivo evaluation of Nb-90 labeled biomolecules is planned. We will evaluate the in vivo behavior of full length antibodies as well of antibody fragments. Three well established PET isotopes will be applied as references, Zr-89 (T½ = 78.4 h) for long pharmacokinetic processes and Ga-68 (T1/2 = 67.7 min) and Sc-44 (T1/2 = 3.92 h) for antibody fragments. To attach the isotopes to biomolecules, the same bifunctional chelator desferrioxamine is considered as the ligand of choice.