Boosting Bismuth(III) Complexation for Targeted α‐Therapy (TAT) Applications with the Mesocyclic Chelating Agent AAZTA**

Abstract

Targeted α therapy (TAT) is a promising tool in the therapy of cancer. The radionuclide 213BiIII shows favourable physical properties for this application, but the fast and stable chelation of this metal ion remains challenging. Herein, we demonstrate that the mesocyclic chelator AAZTA quickly coordinates BiIII at room temperature, leading to a robust complex. A comprehensive study of the structural, thermodynamic and kinetic properties of [Bi(AAZTA)]− is reported, along with bifunctional [Bi(AAZTA‐C4‐COO−)]2− and the targeted agent [Bi(AAZTA‐C4‐TATE)]−, which incorporates the SSR agonist Tyr3‐octreotate. An unexpected increase in the stability and kinetic inertness of the metal chelate was observed for the bifunctional derivative and was maintained for the peptide conjugate. A cyclotron‐produced 205/206Bi mixture was used as a model of 213Bi in labelling, stability, and biodistribution experiments, allowing the efficiency of [213Bi(AAZTA‐C4‐TATE)]− to be estimated. High accumulation in AR42J tumours and reduced kidney uptake were observed with respect to the macrocyclic chelate [213Bi(DOTA‐TATE)]−.

Unravelling the 6sp ← 6s absorption spectra of Bi(iii) complexes

“…Most preclinical studies have used DTPA (diethylenetriaminepentaacetic acid) derivatives for this purpose, 6 but other polyaminopolycarboxylate chelators are currently being developed for this application, as the complexes of acyclic ligands such as DTPA at times present lower stability compared with cyclic analogues such as DOTA (1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid). 7–14…”

“…Most preclinical studies have used DTPA (diethylenetriaminepentaacetic acid) derivatives for this purpose, 6 but other polyaminopolycarboxylate chelators are currently being developed for this application, as the complexes of acyclic ligands such as DTPA at times present lower stability compared with cyclic analogues such as DOTA (1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid). [7][8][9][10][11][12][13][14] The Bi(III) ion has a [Xe]4f 14 5d 10 6s 2 electron configuration, shared as well with Pb(II) and Tl(I). The coordination chemistry of these metal ions is heavily impacted by the lone-pair effect, 12,[15][16][17][18] which refers to the reluctance of the 6s 2 electrons to be ionized or participate in chemical bonding.…”

Rigid H4OCTAPA derivatives as model chelators for the development of Bi(iii)-based radiopharmaceuticals

“…These results are similar to those reported recently for acyclic chelates. 15,19,20 However, H 4 OCTAPA showed lower radiolabelling yields at 2 μM (82%) at 37 °C and 95 °C (89%).…”

“…To overcome this, cyclic and acyclic ligands of various types have been used for this purpose. 8,[11][12][13][14][15] Most of them share the use of oxygen and nitrogen as donor atoms. Usually, cyclic ligands are characterised by slow kinetics of complexation, but they offer higher inertness than acyclic ones.…”