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: Tb-149, Tb-152, Tb-155, and Tb-161. The identical chemical characteristics of these radioisotopes allow the preparation of radiopharmaceuticals with identical pharmacokinetics useful for PET (Tb-152) and SPECT diagnosis (Tb-155) and for alpha- (Tb-149) and beta(-)-particle (Tb-161) 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: Tb-161 was produced by irradiation of Gd-160 targets with neutrons at Paul Scherrer Institute or Institut Laue-Langevin. After neutron capture, the short-lived Gd-161 decays to Tb-161. Tb-149, (152)To, and Tb-155 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 experimets with Tb-149-cm09 and Tb-161-cm09 were performed in KB tumor-bearing nude mice. Diagnostic PET/CT (Tb-152-cm09) and SPECT/CT (Tb-155-cm09 and Tb-161-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 (149)-Tb) to approximately 15 GBq (for Tb-161). 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, similar to 15; tumor to liver, similar to 5.9; and tumor to kidney, similar to 0.8) allowed the visualization of tumors in mice using PET (Tb-152-cm09) and SPECT (Tb-155-cm09 and Tb-161-cm09). Compared with no therapy, alpha- (Tb-149-cm09) and beta(-)-particle therapy (Tb-161-cm09) resulted in a marked delay in tumor growth or even complete remission (33% for Tb-149-cm09 and 80% for Tb-161-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 Tb-152 PET and Tb-155 SPECT, we demonstrated the therapeutic efficacy of the alpha-emitter Tb-149 and beta(-)-emitter Tb-161.