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 ²¹³ Bi^III 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 Bi^III 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 ^205/206 Bi mixture was used as a model of ²¹³ Bi in labelling, stability, and biodistribution experiments, allowing the efficiency of [²¹³ Bi(AAZTA-C4-TATE)]^- to be estimated. High accumulation in AR42J tumours and reduced kidney uptake were observed with respect to the macrocyclic chelate [²¹³ Bi(DOTA-TATE)]^- .

Keywords: AAZTA; Bioconjugation; Bismuth; Octreotate; Targeted Alpha Therapy.

Figure 1

Bi^III‐complexes for biomedical applications.

Figure 2

AAZTA, bifunctional derivatives and conjugates.

Figure 3

Preparation of AAZTA‐C4‐TATE.

Figure 4

Stick representation of the Bi^III coordination environment in [Bi(AAZTA)]⁻ (A and B) and [Bi(HAAZTA)(H₂O)] complexes found in the single crystals of [Bi(HAAZTA)(H₂O)] ⋅ 3H₂O and {[C(NH₂)₃][Bi(AAZTA)]} ⋅ 3.5H₂O.

Figure 5

Labelling yield of AAZTA‐C4‐TATE with ^205/206Bi as a function of [AAZTA‐C4‐TATE] at 25 °C (A) and 95 °C (B) in 5 min reaction time. (pH=3 (•), 4 (•), 5 (•), 6 (•) and 7 (•)). Reaction volume was 100 μL and the activity of reactions was around 0.1 MBq.

Figure 6

Stability investigation of [^205/206Bi(AAZTA‐C4‐TATE)]⁻ in PBS (•) and 0.01 M DTPA (•) solutions at room temperature, and in human plasma (•) at 37 °C. The activity of the reaction mixtures was around 0.017 MBq and the reaction volume was 30 μL for DTPA and PBS stability and 100 μL for plasma stability.

Figure 7

Ex vivo biodistribution of [^205/206Bi(AAZTA‐C4‐TATE]⁻ in AR42 J somatostatine receptor positive tumour‐bearing CB17 SCID mice 15, 60 and 90 min after intravenous injection of the radiotracer. %ID/g values are presented as mean±SD.