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.

New multiple myeloma (MM) treatments—such as high-dose melphalan therapy plus autologous stem cell transplantation or regimens incorporating bortezomide, thalidomide, and lenalidomide—substantially increase the rate of complete response that is associated with longer patient survival. Thus, maintaining the complete response status by improving the minimal residual disease after induction therapy is a key goal for MM management. Here, we address the question of radioimmunotherapy efficacy in MM minimal residual disease treatment in mice with a low tumor burden. α-emitters are particularly well adapted to this approach because the short range of α-particles enables localized irradiation of tumor cells within the bone marrow and a cytotoxic effect on isolated cells due to the high LET (linear energy transfer) of α-particles. The CD138 antigen was used as a target because of its strong expression on myeloma cells in 100% of patients. Method: Intravenous injection of 10⁶ 5T33 mouse myeloma cells into the Syngeneic mouse strain C57BL/KaLwRij resulted in a rapid invasion of the marrow and limb paralysis, as illustrated by bioluminescence imaging with luciferase-transfected 5T33 cells. Radioimmunotherapy was performed 10 d after 5T33 cell engraftment with an intravenous injection of an antimouse CD138 antibody radiolabeled with ²¹³Bi at activities of 1.85, 3.7, 7.4, and 11.1 MBq. A blood cell count was performed weekly to monitor hematologic toxicity. The levels of blood Flt3 ligand were also measured to evaluate the radioimmunotherapy-related myelotoxicity. Disease progression was monitored by titrating the monoclonal IgG2b antibody produced by 5T33 cells. Results: The groups treated with 3.7 and 7.4 MBq exhibited a median survival greater than 300 and 227 d, respectively, compared with 45.5 d in the control untreated group. The highest activity (11.1 MBq) showed short-term toxicity whereas the lowest activity (1.85 MBq) gave results similar to those of the controls. With activities of 3.7 and 7.4 MBq, mice exhibited a transient hematologic toxicity whereas only temporary and moderate myelotoxicity was observed with 7.4 MBq. Conclusion: This study demonstrates promising therapeutic efficacy of ²¹³Bi-labeled anti-mCD138 for the treatment of residual disease in the case of MM, with only moderate and transient toxicity.

Personalized medicine represents a major goal in oncology. It has its underpinning in the identification of biomarkers with diagnostic, prognostic, or predictive values. Nowadays, the concept of biomarker no longer necessarily corresponds to biological characteristics measured ex vivo but includes complex physiological characteristics acquired by different technologies. Positron-emission-tomography (PET) imaging is an integral part of this approach by enabling the fine characterization of tumor heterogeneity in vivo in a non-invasive way. It can effectively be assessed by exploring the heterogeneous distribution and uptake of a tracer such as 18F-fluoro-deoxyglucose (FDG) or by using multiple radiopharmaceuticals, each providing different information. These two approaches represent two avenues of development for the research of new biomarkers in oncology. In this article, we review the existing evidence that the measurement of tumor heterogeneity with PET imaging provide essential information in clinical practice for treatment decision-making strategy, to better select patients with poor prognosis for more intensive therapy or those eligible for targeted therapy.

Recent advances in molecular characterization of tumors have allowed identification of new molecular targets on tumor cells or biomarkers. In medical practice, the identification of these biomarkers slowly but surely becomes a prerequisite before any treatment decision, leading to the concept of personalized medicine. Immuno-positron emission tomography (PET) fits perfectly with this approach. Indeed, monoclonal antibodies (mAbs) labelled with radionuclides represent promising probes for theranostic approaches, offering a non-invasive solution to assess in vivo target expression and distribution. Immuno-PET can potentially provide useful information for patient risk stratification, diagnosis, selection of targeted therapies, evaluation of response to therapy, prediction of adverse effects or for titrating doses for radioimmunotherapy. This paper reviews some aspects and recent developments in labelling methods, biological targets, and clinical data of some novel PET radiopharmaceuticals.

This paper reviews some aspects and recent developments in the use of antibodies to target radionuclides for tumor imaging and therapy. While radiolabeled antibodies have been considered for many years in this context, only a few have reached the level of routine clinical use. However, alternative radionuclides, with more appropriate physical properties, such as lutetium-177 or copper-67, as well as alpha-emitting radionuclides, including astatine-211, bismuth-213, actinium-225, and others are currently reviving hopes in cancer treatments, both in hematological diseases and solid tumors. At the same time, PET imaging, with short-lived radionuclides, such as gallium-68, fluorine-18 or copper-64, or long half-life ones, particularly iodine-124 and zirconium-89 now offers new perspectives in immuno-specific phenotype tumor imaging. New antibody analogues and pretargeting strategies have also considerably improved the performances of tumor immunotargeting and completely renewed the interest in these approaches for imaging and therapy by providing theranostics, companion diagnostics and news tools to make personalized medicine a reality.

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.