Heavy Alkaline Earth Radiometals for Cancer Theranostics: Coordination and Radiochemistry of Radium-223 and...

Area of Science:

• Coordination chemistry
• Radiochemistry
• Nuclear medicine

Background:

• Targeted alpha therapy (TAT) using α-emitters like radium-223 (²²³Ra) offers precise cancer treatment.
• SPECT imaging with γ-emitters like barium-131 (¹³¹Ba) enables treatment monitoring.
• Stable chelation of Ra²⁺/Ba²⁺ is crucial for developing theranostic agents but remains a significant challenge.

Purpose of the Study:

• To design and synthesize novel macrocyclic chelators for Ra²⁺/Ba²⁺.
• To evaluate the thermodynamic and structural properties of the chelator complexes.
• To assess the potential of these chelators for ²²³Ra/¹³¹Ba radiolabeling in cancer theranostics.

Main Methods:

• Synthesis of four functionalized 1,10-diaza-18-crown-6 (Kryptofix 22) derivatives: macrophospho, macromal, macrocat, and macroHOPO.
• Thermodynamic and structural characterization using potentiometry, NMR spectroscopy, X-ray crystallography, and DFT calculations.
• Radiolabeling studies with ²²³Ra and ¹³¹Ba under varying conditions.

Main Results:

• Macromal exhibited the highest stability constant for a 1:1 Ba²⁺ complex (logβ = 16.6), surpassing the current state-of-the-art chelator.
• The order of experimental complex stability was determined as macromal > macropa ≫ macrophospho ∼ macroHOPO > macrocat.
• Quantitative ²²³Ra/¹³¹Ba incorporation was not achieved, but the study expanded the coordination chemistry of these heavy alkaline earth metals.

Conclusions:

• Novel macrocyclic chelators were developed, with macromal showing exceptional stability for Ba²⁺/Ra²⁺ complexation.
• This research contributes valuable insights into the coordination chemistry of Ra²⁺/Ba²⁺, essential for advancing theranostic applications.
• Further optimization is needed to achieve quantitative radiolabeling for clinical translation of ²²³Ra/¹³¹Ba theranostics.