The Evolving Coordination Chemistry of Radiometals for Targeted Alpha Therapy

Abstract

Several radiometals are of interest in the development of new a-emitting radiopharmaceuticals. This review highlights the role of coordination chemistry in the design of 225 Ac, 212/213 Bi, 212 Pb, 149 Tb, 227 Th, and 223/224 Ra radiopharmaceuticals to treat cancer. Several chelators have recently been developed that are addressing the specific requirements of each radiometal to provide outstanding radiolabelling and in vivo properties. These advances are supporting the momentum that is building around radiopharmaceuticals for targeted a therapy.

Alpha-Emitting Radionuclides: Current Status and Future Perspectives

“…The key criteria for the choice of alpha-particle-emitting radionuclides are the half-life, the stable binding to a chelating system, the particle energy, the possible decay chain properties, and the kinetics of the daughters, as well as the costs and availability. These features result in a small number of radionuclides that are suitable, including thorium-227, actinium-225, radium-223/-224, bismuth-212/-213, astatine-211, and terbium-149 [ 14 , 15 ]. Additionally, lead-212 can be mentioned in this list, while delivering one beta particle prior to the alpha decay.…”

“…In aqueous environments, Pb is primarily found as a bivalent cation in the oxidation state +2. The most frequently used chelators for radioconjugate preparation are DOTA [ 52 ] and TCMC or DOTAM (1,4,7,10-tetraaza-1,4,7,10-tetra(2-carbamoylmethyl)cyclododecane) and the derivatives thereof, whereas DOTAM seems to have a higher in vivo stability compared to DOTA [ 14 ]. A total CN of 8 was found in the Pb complexes of the standard chelators DOTA, DOTAM, or DTPA with high log K values of >18.…”

Theranostic Nuclear Medicine with Gallium-68, Lutetium-177, Copper-64/67, Actinium-225, and Lead-212/203 Radionuclides

“…238 Despite this complication, DOTA and TCMC (also known as DOTAM) (1,4,7,10tetrakis(carbamoylmethyl)-1,4,7,10-tetraazacyclododecane), where the carboxylate arms are modified to carbamoylmethyl groups, remain the two most used chelators for the [ 212 Pb]Pb II /[ 203 Pb]Pb II pair to date, although others are in early stages of development. 239,240 Both have been conjugated to small molecules, 231,241 peptides, 234,242 and antibodies. 243−245 The therapeutic efficacy of DOTAMTATE (Figure 28) radiolabeled with lead-212 was evaluated in AR42J neuroendocrine tumor models.…”

“…For example, as [ 212 Pb]­Pb­(DOTA) decays to [ 212 Bi]­Bi­(DOTA), 35% of the bismuth ion is released from the ligand due to the formation of highly ionized Bi V and Bi VII as a result of the internal conversion process . Despite this complication, DOTA and TCMC (also known as DOTAM) (1,4,7,10-tetrakis­(carbamoylmethyl)-1,4,7,10-tetraazacyclododecane), where the carboxylate arms are modified to carbamoylmethyl groups, remain the two most used chelators for the [ 212 Pb]­Pb II /[ 203 Pb]­Pb II pair to date, although others are in early stages of development. , Both have been conjugated to small molecules, , peptides, , and antibodies. − The therapeutic efficacy of DOTAMTATE (Figure ) radiolabeled with lead-212 was evaluated in AR42J neuroendocrine tumor models . Fractionated dosing showed a promising 100% survival rate when 3 × 555 kBq were administered over 2 or 3 week intervals with a combination of 5-fluorouracil to maximize tumor devastation.…”

Macrocyclic 1,2-Hydroxypyridinone-Based Chelators as Potential Ligands for Thorium-227 and Zirconium-89 Radiopharmaceuticals

“…Among the radionuclides considered for TAT, thorium-227 ( 227 Th) has shown significant promise for this application. − In its decay to stable lead-207 ( 207 Pb), 227 Th produces five high-energy α particles, which cause DNA double-strand breaks and subsequent cell death. , The 18.7-day half-life ( t 1/2 ) of 227 Th is suitable for use with antibody-based targeting vectors that have a long circulation time in vivo. Another benefit of 227 Th for targeted radiotherapy is that the γ-rays emitted by this radionuclide may be used to quantitatively assess the distribution of the administered radiotherapeutic agent and the progress of the treatment in vivo using single-photon emission computed tomography/computed tomography (SPECT/CT) imaging. , Lastly, 227 Th is the parent isotope of 223 Ra, meaning that established strategies currently used for the production of 223 Ra can be directly applied to generation of 227 Th, − suggesting that sufficient quantities of this radioisotope may be available to sustain preclinical and clinical studies.…”