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 161Tbcm09) 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 MBq (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. Copyright © 2012 by the Society of Nuclear Medicine and Molecular Imaging, Inc.