A Unique Matched Quadruplet of Terbium Radioisotopes for PET and SPECT and for α- and β−-Radionuclide Therapy: An In Vivo Proof-of-Concept Study with a New Receptor-Targeted Folate Derivative

Terbium offers 4 clinically interesting radioisotopes with complementary physical decay characteristics: 149Tb, 152Tb, 155Tb, and 161Tb. The identical chemical characteristics of these radioisotopes allow the preparation of radiopharmaceuticals with identical pharmacokinetics useful for PET (152Tb) and SPECT diagnosis (155Tb) and for α- (149Tb) and β−-particle (161Tb) therapy. The goal of this proof-of-concept study was to produce all 4 terbium radioisotopes and assess their diagnostic and therapeutic features in vivo when labeled with a folate-based targeting agent. Methods: 161Tb was produced by irradiation of 160Gd targets with neutrons at Paul Scherrer Institute or Institut Laue-Langevin. After neutron capture, the short-lived 161Gd decays to 161Tb. 149Tb, 152Tb, and 155Tb were produced by proton-induced spallation of tantalum targets, followed by an online isotope separation process at ISOLDE/CERN. The isotopes were purified by means of cation exchange chromatography. For the in vivo studies, we used the DOTA–folate conjugate cm09, which binds to folate receptor (FR)–positive KB tumor cells. Therapy experiments with 149Tb-cm09 and 161Tb-cm09 were performed in KB tumor–bearing nude mice. Diagnostic PET/CT (152Tb-cm09) and SPECT/CT (155Tb-cm09 and 161Tb-cm09) studies were performed in the same tumor mouse model. Results: Carrier-free terbium radioisotopes were obtained after purification, with activities ranging from approximately 6 MBq (for 149Tb) to approximately 15 GBq (for 161Tb). The radiolabeling of cm09 was achieved in a greater than 96% radiochemical yield for all terbium radioisotopes. Biodistribution studies showed high and specific uptake in FR-positive tumor xenografts (23.8% ± 2.5% at 4 h after injection, 22.0% ± 4.4% at 24 h after injection, and 18.4% ± 1.8% at 48 h after injection). Excellent tumor-to-background ratios at 24 h after injection (tumor to blood, ∼15; tumor to liver, ∼5.9; and tumor to kidney, ∼0.8) allowed the visualization of tumors in mice using PET (152Tb-cm09) and SPECT (155Tb-cm09 and 161Tb-cm09). Compared with no therapy, α- (149Tb-cm09) and β−-particle therapy (161Tb-cm09) resulted in a marked delay in tumor growth or even complete remission (33% for 149Tb-cm09 and 80% for 161Tb-cm09) and a significantly increased survival. Conclusion: For the first time, to our knowledge, 4 terbium radionuclides have been tested in parallel with tumor-bearing mice using an FR targeting agent. Along with excellent tumor visualization enabled by 152Tb PET and 155Tb SPECT, we demonstrated the therapeutic efficacy of the α-emitter 149Tb and β−-emitter 161Tb.