Background Phenanthroline derivatives are well-known chelators in coordination chemistry, but their potential in the rapidly evolving field of targeted radionuclide therapy (TRT) has not yet been explored. In TRT, DOTA remains the gold standard chelator for several clinically relevant radionuclides such as terbium-161, lutetium-177 and bismuth-213. However, its requirement for elevated labeling temperatures is a drawback, particularly for heat-sensitive targeting vectors. Although several alternative chelators have been reported in recent years, there remains an interest in new systems with suitable complexation properties. In this work, we evaluate whether phenanthroline-based ligands can serve as useful chelators in TRT, using the octadentate chelator H4FENTA and a newly developed bifunctional analog, BF-FENTA. Their ability to complex [161Tb]Tb3+, [177Lu]Lu3+, and [213Bi]Bi3+, as well as their kinetic inertness, was assessed and compared to the benchmark chelators DOTA and CHX-A”-DTPA. Results BF-FENTA was prepared via mono-substitution of 2,9-bis(chloromethyl)-1,10-phenanthroline with di-tert-butyl iminodiacetate, followed by a second substitution with the bifunctional arm. Both H4FENTA and BF-FENTA efficiently incorporated [161Tb]Tb3+ under mild conditions within 15 min at an apparent molar activity (AMA) of 150 MBq/nmol. Stability studies showed that both chelators formed an unstable complex with [161Tb]Tb3+, while the [177Lu]Lu3+ chelates showed similar stability compared to DOTA after 7 days in human serum. However, a DTPA challenge indicated a reduced kinetic inertness for both FENTA chelators compared to DOTA. For [213Bi]Bi3+, rapid incorporation was observed with the phenanthroline chelators, with H4FENTA achieving high radiochemical conversions (> 90%) at high AMAs of up to ~ 200 MBq/nmol after 5 min. Additionally, H4FENTA displayed a high selectivity for [213Bi]Bi3+ in the presence of competing metal ions. BF-FENTA showed slightly less favorable chelation properties with [213Bi]Bi3+ compared to H4FENTA. Nonetheless, the [213Bi]Bi3+ complexes remained intact in both buffer (NH4OAc, pH 6.0) and human serum after 90 min. Conclusion Both H4FENTA and BF-FENTA rapidly incorporated terbium-161, lutetium-177, and bismuth-213. While the kinetic inertness of their terbium-161 and lutetium-177 complexes was inadequate, H4FENTA exhibited favorable kinetic inertness with bismuth-213 over the 90 min timeframe, identifying it as a promising chelator. In contrast, further structural refinement is needed for its bifunctional analog.

Radiolabeling efficiency of FENTA chelators and stability of their terbium-161, lutetium-177 and bismuth-213 complexes

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2026年4月7日

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Cédric Bonneux,
Sunay Rodríguez Pérez,
Stephan Heinitz,
Veronique Bogaerts,
Michiel Van de Voorde,
Thomas Cardinaels,
Maarten Ooms,
Wim Dehaen,
Tomas Opsomer

摘要

Background

Phenanthroline derivatives are well-known chelators in coordination chemistry, but their potential in the rapidly evolving field of targeted radionuclide therapy (TRT) has not yet been explored. In TRT, DOTA remains the gold standard chelator for several clinically relevant radionuclides such as terbium-161, lutetium-177 and bismuth-213. However, its requirement for elevated labeling temperatures is a drawback, particularly for heat-sensitive targeting vectors. Although several alternative chelators have been reported in recent years, there remains an interest in new systems with suitable complexation properties. In this work, we evaluate whether phenanthroline-based ligands can serve as useful chelators in TRT, using the octadentate chelator H₄FENTA and a newly developed bifunctional analog, BF-FENTA. Their ability to complex [¹⁶¹Tb]Tb³⁺, [¹⁷⁷Lu]Lu³⁺, and [²¹³Bi]Bi³⁺, as well as their kinetic inertness, was assessed and compared to the benchmark chelators DOTA and CHX-A”-DTPA.

Results

BF-FENTA was prepared via mono-substitution of 2,9-bis(chloromethyl)-1,10-phenanthroline with di-tert-butyl iminodiacetate, followed by a second substitution with the bifunctional arm. Both H₄FENTA and BF-FENTA efficiently incorporated [¹⁶¹Tb]Tb³⁺ under mild conditions within 15 min at an apparent molar activity (AMA) of 150 MBq/nmol. Stability studies showed that both chelators formed an unstable complex with [¹⁶¹Tb]Tb³⁺, while the [¹⁷⁷Lu]Lu³⁺ chelates showed similar stability compared to DOTA after 7 days in human serum. However, a DTPA challenge indicated a reduced kinetic inertness for both FENTA chelators compared to DOTA. For [²¹³Bi]Bi³⁺, rapid incorporation was observed with the phenanthroline chelators, with H₄FENTA achieving high radiochemical conversions (> 90%) at high AMAs of up to ~ 200 MBq/nmol after 5 min. Additionally, H₄FENTA displayed a high selectivity for [²¹³Bi]Bi³⁺ in the presence of competing metal ions. BF-FENTA showed slightly less favorable chelation properties with [²¹³Bi]Bi³⁺ compared to H₄FENTA. Nonetheless, the [²¹³Bi]Bi³⁺ complexes remained intact in both buffer (NH₄OAc, pH 6.0) and human serum after 90 min.

Conclusion

Both H₄FENTA and BF-FENTA rapidly incorporated terbium-161, lutetium-177, and bismuth-213. While the kinetic inertness of their terbium-161 and lutetium-177 complexes was inadequate, H₄FENTA exhibited favorable kinetic inertness with bismuth-213 over the 90 min timeframe, identifying it as a promising chelator. In contrast, further structural refinement is needed for its bifunctional analog.