title: 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.
abstract: Terbium offers 4 clinically interesting radioisotopes with complementary physical decay characteristics: (149)Tb, (152)Tb, (155)Tb, and (161)Tb. The identical chemical characteristics of these radioisotopes allow the preparation of radiopharmaceuticals with identical pharmacokinetics useful for PET ((152)Tb) and SPECT diagnosis ((155)Tb) and for α- ((149)Tb) and β(-)-particle ((161)Tb) 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
  (161)Tb was produced by irradiation of (160)Gd targets with neutrons at Paul Scherrer Institute or Institut Laue-Langevin. After neutron capture, the short-lived (161)Gd decays to (161)Tb. (149)Tb, (152)Tb, and (155)Tb 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 (149)Tb-cm09 and (161)Tb-cm09 were performed in KB tumor-bearing nude mice. Diagnostic PET/CT ((152)Tb-cm09) and SPECT/CT ((155)Tb-cm09 and (161)Tb-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 MBq (for (161)Tb). 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 ((152)Tb-cm09) and SPECT ((155)Tb-cm09 and (161)Tb-cm09). Compared with no therapy, α- ((149)Tb-cm09) and β(-)-particle therapy ((161)Tb-cm09) resulted in a marked delay in tumor growth or even complete remission (33% for (149)Tb-cm09 and 80% for (161)Tb-cm09) and a significantly increased survival.
  
  
  CONCLUSIONS
  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 (152)Tb PET and (155)Tb SPECT, we demonstrated the therapeutic efficacy of the α-emitter (149)Tb and β(-)-emitter (161)Tb.
authors.affiliation: Center for Radiopharmaceutical Sciences ETH-PSI-USZ, Paul Scherrer Institute, Villigen-PSI, Switzerland.
authors.forename: Cristina
authors.initials: C
authors.lastname: Müller
authors.forename: Konstantin
authors.initials: K
authors.lastname: Zhernosekov
authors.forename: Ulli
authors.initials: U
authors.lastname: Köster
authors.forename: Karl
authors.initials: K
authors.lastname: Johnston
authors.forename: Holger
authors.initials: H
authors.lastname: Dorrer
authors.forename: Alexander
authors.initials: A
authors.lastname: Hohn
authors.forename: Nico T
authors.initials: NT
authors.lastname: van der Walt
authors.forename: Andreas
authors.initials: A
authors.lastname: Türler
authors.forename: Roger
authors.initials: R
authors.lastname: Schibli
mesh_terms: D000512:Alpha Particles / Q000627:therapeutic use; D000818:Animals; D001610:Beta Particles / Q000627:therapeutic use; D005260:Female; D058973:Folate Receptors, GPI-Anchored / Q000378:metabolism; D005492:Folic Acid / Q000737:chemistry / Q000378:metabolism* / Q000627:therapeutic use; D006573:Heterocyclic Compounds, 1-Ring / Q000737:chemistry; D006801:Humans; D007624:KB Cells; D051379:Mice; D049268:Positron-Emission Tomography / Q000379:methods*; D011868:Radioisotopes / Q000627:therapeutic use*; D013725:Terbium / Q000627:therapeutic use*; D015899:Tomography, Emission-Computed, Single-Photon / Q000379:methods*
chemical_list: D058973:Folate Receptors, GPI-Anchored; D006573:Heterocyclic Compounds, 1-Ring; D011868:Radioisotopes; D013725:Terbium; C071349:1,4,7,10-tetraazacyclododecane- 1,4,7,10-tetraacetic acid; D005492:Folic Acid