Insights into Actinium Complexes with Tetraacetates─AcBATA versus AcDOTA: Thermodynamic, Structural, and Labeling Properties

Abstract

In the current research, we conducted a comparative study of the Ac 3+ complex with H 4 DOTA and H 4 BATA. The stability constants of the [AcBATA] − and [AcDOTA] − complexes were studied directly by extraction methods. We discovered that the thermodynamic properties of the [AcBATA] − complex are superior to those of [AcDOTA] − . Moreover, the fast kinetics of H 4 BATA complexation with Ac 3+ during the radiolabeling experiment was observed already at room temperature. Ac 3+ was placed inside the macrocyclic cavity of the [AcBATA] − complex, preventing the release of the cation. According to DFT studies, two possible conformations were found, where two pendant arms coordinate with the metal cation on one side of the azacrown cavity and two on the other side, or three pendant arms are located on one side and one on the other. Finally, high inertness in vitro and in vivo of [AcBATA] − was discovered, making the H 4 BATA ligand highly preferable for application as a component of actinium-based radiopharmaceuticals.

Actinium chelation and crystallization in a macromolecular scaffold

“…The error reported is the standard deviation corresponding to the last digit in triplicate measurements. f The cumulative stability constant (log ) of HOPO–Scn with Ac III compared to other chelators, including DOTA 19 , BATA 19 , and EDTA 45 . The asterisk denotes a conditional stability constant.…”

“…The conditional stability constant of the [Ac III (HOPO)] 1– complex, with a log value of 17.0(1), expands the very limited library of actinium thermodynamic data 14 . Put in the context of other chelators, the [Ac III (HOPO)] 1– formation constant is greater than that of ethylenediaminetetraacetic acid (EDTA), with a log value of 14.22 ( I = 0.1 M, pH = 2.8) 45 , and is less than the formation constants of Ac III with 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (H 4 DOTA) and H 4 BATA with log values of 20.32(3) and 25.74(1), respectively 19 . The lanthanide-utilizing protein lanmodulin (LanM) has been shown to recognize actinium, with a polymetallic formation constant of 36.2(5) for 228 Ac 3 LanM at pH 7, but should be noted as the product of three individual stability constants, one for each metal binding site 22 .…”

“…Despite its discovery at the turn of the century, little research has been dedicated to understanding actinium (Ac) chemistry over the past several decades, with only a handful of studies reported with simple inorganic or organic ligands 14 . Interest in fundamental Ac coordination has experienced a revival due to the recent realization of the potential of 225 Ac for TAT 15 – 19 , yet developments are scarce as the chemistry is technically challenging, requires specialized facilities, and is currently limited to scales of micrograms or less due to the current production capabilities for 225 Ac and other Ac isotopes 11 , 20 . Nonetheless, important advancements have been made in the theoretical and experimental gas- and solution-state chelation of Ac with synthetic and naturally occurring systems, in addition to pioneering X-ray absorption spectroscopic measurements to probe its coordination behavior in relevant solutions 21 – 26 .…”

Towards Clinical Development of Scandium Radioisotope Complexes for Use in Nuclear Medicine: Encouraging Prospects with the Chelator 1,4,7,10-Tetraazacyclododecane-1,4,7,10-tetraacetic Acid (DOTA) and Its Analogues

“…Many chelators are potential candidates for stable scandium complex formation in vitro but only a few are effective in vivo. In particular, 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA) and some of its analogues appear to be a leading and promising group of chelators that form stable complexes with a variety of transition and rare earth metals, which, in turn, exhibit high stability under physiological conditions [ 19 , 20 , 21 ]. Most importantly, promising results from many in vitro and in vivo studies, as well as preliminary clinical findings, suggest that Sc-DOTA complexes are promising for further development in diagnostic and theranostic applications in cancer patients and nuclear medicine in general.…”

Formation of an Unusual Pseudo-Square Planar-Induced Mercury(II) Dimeric Complex

“…Macrocyclic ligands play a critical role in supramolecular coordination chemistry due to their specific ability to selectively bind and self-assemble with particular metals or guest molecules [1][2][3][4][5][6][7][8][9][10][11][12][13][14][15][16]. This selectivity is the result of their unique structure, which forms a cyclic cavity that can accommodate specific species.…”