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²¹¹At- and ¹³¹I-Labeled Bisphosphonates with High In Vivo Stability and Bone Accumulation

Department of Chemistry, University of Oslo, Oslo
Department of Oncology, The Norwegian Radium Hospital, Oslo, Norway
Department of Radiology, Duke University Medical Center, Durham, North Carolina

Correspondence: For correspondence or reprints contact: Roy H. Larsen, PhD, Department of Chemistry, University of Oslo, P.O. Box 1033, Blindem, 0315 Oslo, Norway.

ABSTRACT

Bisphosphonates were synthesized for use as carriers for astatine and iodine radioisotopes to target bone neoplasms. Methods: Radiohalogenated activated esters were coupled to the amino group in the side chain of the bisphosphonate. The bisphosphonate 3-amino-1-hydroxypropylidene bisphosphonate was combined with four different acylation agents: N-succinimidyl 3-[²¹¹At]astatobenzoate, N-succinimidyl 3-[¹³¹I]iodobenzoate, N-succinimidyl-5-[²¹¹At]astato-3-pyridinecarboxylate and N-succinimidyl-5-[¹³¹l]iodo-5-pyridinecarboxylate. The products, 3-[¹³¹I]iodobenzamide-N-3-hydroxypropylidene-3,3-bisphosphonate (IBPB), 3-[²¹¹At]astato-benzamide-N-3-hydroxypropylidene-3,3-bisphosphonate (ABPB), 5-[¹³¹I]iodopyridine-3-amide-N-3-hydroxypropylidene-3,3-bisphosphonate (IPPB) and 5-[²¹¹At]astatopyridine-3-amide-N-3-hydroxypropylidene-3,3-bisphosphonate (APPB), were injected intravenously into Balb/c mice. MIRD and Monte Carlo methods were used on the basis of cumulated activity calculated from biodistribution data to estimate dose to organs and bone segments. Results: All ¹³¹I-and ²¹¹At-labeled analogs were strongly incorporated into osseous tissue and retained there at stable levels, while a rapid clearance from blood was observed. The bone uptake was found to be similar for ²¹¹At- and ¹³¹I-labeled bisphosphonate when compared in paired label experiments. Bone uptake and bone-to tissue ratios were better for IBPB compared with IPPB, and ABPB compared with APPB. All four compounds appeared to be highly resistant to in vivo dehalogenation as indicated by low uptake of ¹³¹I/²¹¹At in the thyroid gland and stomach. According to dosimetric estimates, the bone surface-to-bone marrow ratio was three times higher with ²¹¹At than with ¹³¹I. Conclusion: Both the ß-particle-and -particle-emitting compounds showed high in vivo stability and excellent affinity for osseous tissue. Further preclinical evaluation is therefore warranted.

Key Words: radiohalogenated bisphosphonates • bone therapy • bone pain

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