Among all existing radionuclides, only a few are of interest for therapeutic applications and more specifically for targeted alpha therapy (TAT). From this selection, actinium-225, astatine-211, bismuth-212, bismuth-213, lead-212, radium-223, terbium-149 and thorium-227 are considered as the most suitable. Despite common general features, they all have their own physical characteristics that make them singular and so promising for TAT. These radionuclides were largely studied over the last two decades, leading to a better knowledge of their production process and chemical behavior, allowing for an increasing number of biological evaluations. The aim of this review is to summarize the main properties of these eight chosen radionuclides. An overview from their availability to the resulting clinical studies, by way of chemical design and preclinical studies is discussed.

Easy access to radioiodinated and ²¹¹At-labelled bio(macro)molecules is essential to develop new strategies in nuclear imaging and targeted radionuclide therapy of cancers. Yet, the labelling of complex molecules with heavy radiohalogens is often poorly effective due to the multiple steps and intermediate purifications needed. Herein, we investigate the potential of arylboron chemistry as an alternative approach for the late stage labelling of antibodies. The reactivity of a model precursor, 4-chlorobenzeneboronic acid (1) with nucleophilic iodine-125 and astatine-211 was at first investigated in aqueous conditions. In the presence of a copper(II) catalyst and 1,10-phenanthroline, quantitative radiochemical yields (RCYs) were achieved within 30 minutes at room temperature. The optimum conditions were then applied to a CD138 targeting monoclonal antibody (mAb) that has previously been validated for imaging and therapy in a preclinical model of multiple myeloma. RCYs remained high (>80% for ¹²⁵I-labelling and >95% for ²¹¹At-labelling), and the whole procedure led to increased specific activities within less time in comparison with previously reported methods. Biodistribution study in mice indicated that targeting properties of the radiolabelled mAb were well preserved, leading to a high tumour uptake in a CD138 expressing tumour model. The possibility of divergent synthesis from a common modified carrier protein demonstrated herein opens facilitated perspectives in radiotheranostic applications with the radioiodine/²¹¹At pairs. Overall, the possibility to develop radiolabelling kits offered by this procedure should facilitate its translation to clinical applications.

211At-radiopharmaceuticals are currently the subject of growing studies for targeted alpha therapy of cancers, which leads to the widening of the scope of the targeting vectors, from small molecules to peptides and proteins. This has prompted, during the past decade, to a renewed interest in developing novel 211At-labelling approaches and novel prosthetic groups to address the diverse scenarios and to reach improved efficiency and robustness of procedures as well as an appropriate in vivo stability of the label. Translated from the well-known (radio)iodine chemistry, the long preferred electrophilic astatodemetallation using trialkylaryltin precursors is now complemented by new approaches using electrophilic or nucleophilic At. Alternatives to the astatoaryl moiety have been proposed to improve labelling stability, and the range of prosthetic groups available to label proteins has expanded. In this report, we cover the evolution of radiolabelling chemistry, from the initial strategies developed in the late 1970’s to the most recent findings.

Te1pa conjugated to an F6 antibody was confirmed to be an interesting alternative to dota for⁶⁴Cuin vivoPET imaging.