Efficient formation of inert Bi-213 chelates by tetraphosphorus acid analogues of DOTA: Towards improved alpha-therapeutics
Abstrakt
Background: The recently growing interest in targeted alpha-therapy (TAT) calls for improvement of the labelling chemistry of the corresponding radionuclides. 213BiIII is a short-lived alpha emitter which emits only one alpha particle in its decay chain. Hence, it might be safer in application than other respective nuclides, such as Ra-223 or Ac-225, because no alpha-emitting daughters are released upon recoil.
We investigated cyclen derivatives with phosphorus-containing pendant arms regarding their suitability for Bi-213 labelling. Results: The concentration dependency of Bi-213 labelling at 25 degrees C and 95 degrees C was determined for DOTP, DOTPH, DOTPEt, and DOTPI, as well as for DOTA and CHX-A"-DTPA for comparison.
The labelling efficiency of the phosphorus-containing ligands was at least comparable to CHX-A"-DTPA and exceeded that of DOTA. DOTP was most efficient, requiring chelator concentrations for labelling which were approx. two orders of magnitude lower than those required for CHX-A"-DTPA, both at 25 degrees C and 95 degrees C.
The Bi-213 complexes of phosphorus ligands furthermore showed a higher stability against demetallation (>96% of intact complex after 120-min incubation in plasma were found for DOTP, DOTPH, and DOTPEt , compared to 85% for DOTA and 76% for CHX-A"-DTPA). Conclusion: Cyclen derivatives bearing four N-methylenephosphonic or -phosphinic acid substituents, e.g., DOTP, are capable of complexing the alpha-emitting radionuclide Bi-213(III) with higher efficiency and in-vitro stability than the current gold standards DOTA and CHX-A"-DTPA.