At-211- and I-131-labeled bisphosphonates with high in vivo stability and bone accumulation

Bisphosphonates were synthesized for use as carriers for astatine and iodin e radioisotopes to target bone neoplasms. Methods: Radiohalogenated activat ed esters were coupled to the amino group in the side chain of the bisphosp honate. The bisphosphonate 3-amino-1-hydroxypropylidene bisphosphonate was combined with four different acylation agents: N-succinimidyl 3-[At-211]ast atobenzoate, N-succinimidyl 3-[I-131]iodobenzoate, N-succinimidyl-5-[At-211 ]astato-3-pyridinecarboxylate and N-succinimidyl-5-[I-131]iodo-5-pyridineca rboxylate. The products, 3-[I-131]iodobenzamide-N-3-hydroxypropylidene-3, 3 -bisphosphonate (IBPB), 3-[At-211]astato-benzamide-N-3-hydroxypropylidene-3 ,3-bisphosphonate (ABPB), 5-[I-131]iodopyridine-3-amide-N-3-hydroxypropylid ene- 3,3-bisphosphonate (IPPB) and 5-[At-211]astatopyridine-3-amide-N-3-hyd roxypropylidene-3,3-bisphosphonate (APPB), were injected intravenously into Balb/c mice. MIRD and Monte Carlo methods were used on the basis of cumula ted activity calculated from biodistribution data to estimate dose to organ s and bone segments. Results: All I-131- and At-211-labeled analogs were st rongly incorporated into osseous tissue and retained there at stable levels , while a rapid clearance from blood was observed. The bone uptake was foun d to be similar for At-211- and I-131-labeled bisphosphonate when compared in paired label experiments. Bone uptake and bone-to-tissue ratios were bet ter for IBPB compared with IPPB, and ABPB compared with APPB. All four comp ounds appeared to be highly resistant to in vivo dehalogenation as indicate d by low uptake of I-131/At-211 in the thyroid gland and stomach. According to dosimetric estimates, the bone surface-to-bone marrow ratio was three t imes higher with At-211 than with I-131. Conclusion: Both the beta-particle - and alpha-particle-emitting compounds showed high in vivo stability and e xcellent affinity for osseous tissue. Further preclinical evaluation is the refore warranted.