pharmaceutics Review Overview of the Most Promising Radionuclides for Targeted Alpha Therapy: The “Hopeful Eight” Romain Eychenne 1,2, * , Michel Chérel 2 ,Férid Haddad 1,3 , François Guérard 2 and Jean-François Gestin 2, *   Citation: Eychenne, R.; Chérel, M.; Haddad, F.; Guérard, F.; Gestin, J.-F. Overview of the Most Promising Radionuclides for Targeted Alpha Therapy: The “Hopeful Eight”. Pharmaceutics 2021, 13, 906. https:// doi.org/10.3390/pharmaceutics13060906 Academic Editor: Yann Seimbille Received: 14 April 2021 Accepted: 8 June 2021 Published: 18 June 2021 Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affil- iations. Copyright: © 2021 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https:// creativecommons.org/licenses/by/ 4.0/). 1 Groupement d’Intérêt Public ARRONAX, 1 Rue Aronnax, F-44817 Saint-Herblain, France; Francehaddad@subatech.in2p3.fr 2 Université de Nantes, Inserm, CNRS, Centre de Recherche en Cancérologie et Immunologie Nantes—Angers (CRCINA)—UMR 1232, ERL 6001, F-44000 Nantes, France; michel.cherel@univ-nantes.fr (M.C.); francois.guerard@univ-nantes.fr (F.G.) 3 Laboratoire Subatech, UMR 6457, Université de Nantes, IMT Atlantique, CNRS, Subatech, F-44000 Nantes, France * Correspondence: eychenne@arronax-nantes.fr (R.E.); jean.francois.gestin@univ-nantes.fr (J.-F.G.) Abstract: 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. Keywords: targeted alpha therapy; α-emitters; actinium-225; astatine-211; bismuth-212; bismuth-213; lead-212; radium-223; terbium-149; thorium-227 1. Introduction Nuclear medicine is a discipline whose applications can have two different purposes: imaging, with visualization of a radionuclide distribution in the organism, or therapy, with specific irradiation of malignant cells. Whatever the intended application, it is mainly based on the administration of drugs defined as radiopharmaceuticals. These radioactive tracers are usually made up of: a radioactive moiety (a unit involving a radionuclide) whose radiations allow localization (γ or β + emitters) or destruction of targeted cells (α, β − or electron Auger emitters); and a molecule to carry it to the target. Unlike imaging that uses radionuclides emitting highly penetrating radiations, radiotherapy favors those that strongly interact with matter leading to low penetration. In that case, α, β − or Auger electron emitters are used to lead to death of malignant cells. This radiopharmaceutical design is at the center of the general concept of targeted radionuclide therapy (TRT) gathering several promising methods such as peptide receptor radionuclide therapy (PRRT) or radioimmunotherapy (RIT) using more specifically β-emitters or α-emitters [1]. The nature of the emitted particle is essential because it has an influence on the induced biological effect. This difference is illustrated by two main features of emitted particle: the path length and the linear energy transfer (LET) [2]. From a biological point of view, irradiation of cells results in direct (by energy transfer, as DNA damage and cross-fire effect) and indirect cellular mechanisms (reactive oxygen species (ROS) generated by water radiolysis and radiation-induced bystander effect (RIBE) described as the spread of signals from irradiated to neighboring cells inducing apoptosis of cells that are not directly exposed Pharmaceutics 2021, 13, 906. https://doi.org/10.3390/pharmaceutics13060906 https://www.mdpi.com/journal/pharmaceutics