Computer-Assisted Design of Macrocyclic Chelators for Actinium-225 Radiotherapeutics

Abstract

Actinium-225 (225Ac) is an excellent candidate for targeted radiotherapeutic applications for treating cancer, because of its 10-day half-life and emission of four high-energy α2+ particles. To harness and direct the energetic potential of actinium, strongly binding chelators that remain stable in vivo during biological targeting must be developed. Unfortunately, controlling chelation for actinium remains challenging. Actinium is the largest +3 cation on the periodic table and has a 6d05f0 electronic configuration, and its chemistry is relatively unexplored. Herein, we present theoretical work focused on improving the understanding of actinium bonding with macrocyclic chelating agents as a function of (1) macrocycle ring size, (2) the number and identity of metal binding functional groups, and (3) the length of the tether linking the metal binding functional group to the macrocyclic backbone. Actinium binding by these chelators is presented within the context of complexation with DOTA4–, the most relevant Ac3+ binding agent for contemporary radiopharmaceutical applications. The results enabled us to develop a new strategy for actinium chelator design. The approach is rooted in our identification that Ac3+–chelation chemistry is dominated by ionic bonding interactions and relies on (1) maximizing electrostatic interactions between the metal binding functional group and the Ac3+ cation and (2) minimizing electronic repulsion between negatively charged actinium binding functional groups. This insight will provide a foundation for future innovation in developing the next generation of multifunctional actinium chelators.

Development of [225Ac]Ac-PSMA-I&T for Targeted Alpha Therapy According to GMP Guidelines for Treatment of mCRPC

“…As described by Miederer et al, 60% of Ac-225 was excreted after injection of [ 227 Ac]Ac-DTPA. Thus, the complexation of the free nuclides could be increased by chelator optimization [ 53 , 54 , 55 , 56 ], opting for 225 Ac-H4py4pa, for example [ 57 ]. However, further research has to be performed regarding this subject.…”

Metal–ligand interactions in complexes of cyclen-based ligands with Bi and Ac

“…The small frozen-core approximation was applied. This level of theory has been used in several recent studies on TAT-related complexes [43][44][45][46]. An auxiliary set of s, p, d, f and g STOs was used to fit the molecular density and to represent the Coulomb and exchange potentials accurately in each SCF cycle.…”

“…We note that some of the above ligands (DOTA, HETA, DOTPA, DOTMP) have recently been included in a study aiming computer-assisted chelator design for 225 Ac [46].…”

“…The 2D structure of each ligand is given in Fig. S1 in the Supplementary Information of Eu-TETA in [73]; and with ligands 11, 12 and 13 from the computed geometries in [46]. We also probed additional isomers of 11 and 12 complexes which then proved to be lower in energy than those published in [46].…”

“…S1 in the Supplementary Information of Eu-TETA in [73]; and with ligands 11, 12 and 13 from the computed geometries in [46]. We also probed additional isomers of 11 and 12 complexes which then proved to be lower in energy than those published in [46]. Complexes with ligand 1 were derived from the optimized geometry of Ac(DOTA) − [72].…”