Pretargeted Nuclear Imaging and Radioimmunotherapy Based on the Inverse Electron-Demand Diels-Alder Reaction and Key Factors in the Pretargeted Synthetic Design.

Lin Qiu,Wujian Mao,Hongyan Yin,Dengfeng Cheng,Hongcheng Shi,Hui Tan

doi:10.1155/2019/9182476

Abstract

The exceptional speed and biorthogonality of the inverse electron-demand Diels–Alder (IEDDA) click chemistry between 1,2,4,5-tetrazines and strained alkene dienophiles have made it promising in the realm of pretargeted imaging and therapy. During the past 10 years, the IEDDA-pretargeted strategies have been tested and have already proven capable of producing images with high tumor-to-background ratios and improving therapeutic effect. This review will focus on recent applications of click chemistry ligations in the pretargeted imaging studies of single photon emission computed tomography (SPECT), positron emission tomography (PET), and pretargeted radioimmunotherapy investigations. Additionally, the influence factors of stability, reactivity, and pharmacokinetic properties of TCO tag modified immunoconjugates and radiolabeled Tz derivatives were also summarized in this article, which should be carefully considered in the system design in order to develop a successful pretargeted methodology. We hope that this review will not only equip readers with a knowledge of pretargeted methodology based on IEDDA click chemistry but also inspire synthetic chemists and radiochemists to develop pretargeted radiopharmaceutical components in a more innovative way with various influence factors considered.

Highlights

Since its advent over a decade and a half ago, click chemistry has been used in most disciplines of modern chemistry, including drug discovery, bioconjugation, materials science, nanoscience, and radiochemistry [1]
We provided a brief introduction about these investigations of pretargeted nuclear imaging and radioimmunotherapy based on inverse electron-demand [4 + 2] Diels–Alder (IEDDA) click reaction
As the singular combination of selectivity, orthogonality, and rapidity of the IEDDA reaction make it almost ideally suited for radiochemical applications, the IEDDA cycloaddition reaction has brought about a significant impact on the field of bioorthogonal radiopharmaceutical chemistry during the past 10 years

Summary

Introduction

Since its advent over a decade and a half ago, click chemistry has been used in most disciplines of modern chemistry, including drug discovery, bioconjugation, materials science, nanoscience, and radiochemistry [1]. E fast IEDDA reaction resulted in high radioactivity accumulation in the expected organs (spleen and liver) within 10 min after the administration of the 18F-Tz. Using the same 18F-labeled Tz as a radiotracer, Keinänen et al [38] investigated pretargeted methodology for tracing two clinically relevant, internalizing mAbs, TCO-modified cetuximab and trastuzumab. Using the same 18F-labeled Tz as a radiotracer, Keinänen et al [38] investigated pretargeted methodology for tracing two clinically relevant, internalizing mAbs, TCO-modified cetuximab and trastuzumab For both antibodies, PET images demonstrated the tumor could be clearly visualized with the highest uptake of 3.7 ± 0.1% ID/g for cetuximab and 1.5 ± 0.1% ID/g for trastuzumab as quantified by ex vivo biodistribution. High kidney uptake (2.5% ID/g 3 h p.i.) was observed, which prevented clinical translation of 212PbDOTA-PEG11-Tz

Stability and Reactivity of Tetrazine and Dienophile

Influence Factors of Pharmacokinetic Properties of mAbTCO

Findings

Summary and Perspective