Production and characterization of no-carrier-added 161Tb as an alternative to the clinically-applied 177Lu for radionuclide therapy

Abstract

Background: ¹⁶¹Tb is an interesting radionuclide for cancer treatment, showing similar decay characteristics and chemical behavior to clinically-employed ¹⁷⁷Lu. The therapeutic effect of ¹⁶¹Tb, however, may be enhanced due to the co-emission of a larger number of conversion and Auger electrons as compared to ¹⁷⁷Lu. The aim of this study was to produce ¹⁶¹Tb from enriched ¹⁶⁰Gd targets in quantity and quality sufficient for first application in patients.

Methods: No-carrier-added ¹⁶¹Tb was produced by neutron irradiation of enriched ¹⁶⁰Gd targets at nuclear research reactors. The ¹⁶¹Tb purification method was developed with the use of cation exchange (Sykam resin) and extraction chromatography (LN3 resin), respectively. The resultant product (¹⁶¹TbCl₃) was characterized and the ¹⁶¹Tb purity compared with commercial ¹⁷⁷LuCl₃. The purity of the final product (¹⁶¹TbCl₃) was analyzed by means of γ-ray spectrometry (radionuclidic purity) and radio TLC (radiochemical purity). The radiolabeling yield of ¹⁶¹Tb-DOTA was assessed over a two-week period post processing in order to observe the quality change of the obtained ¹⁶¹Tb towards future clinical application. To understand how the possible drug products (peptides radiolabeled with ¹⁶¹Tb) vary with time, stability of the clinically-applied somatostatin analogue DOTATOC, radiolabeled with ¹⁶¹Tb, was investigated over a 24-h period. The radiolytic stability experiments were compared to those performed with ¹⁷⁷Lu-DOTATOC in order to investigate the possible influence of conversion and Auger electrons of ¹⁶¹Tb on peptide disintegration.

Results: Irradiations of enriched ¹⁶⁰Gd targets yielded 6-20 GBq ¹⁶¹Tb. The final product was obtained at an activity concentration of 11-21 MBq/μL with ≥99% radionuclidic and radiochemical purity. The DOTA chelator was radiolabeled with ¹⁶¹Tb or ¹⁷⁷Lu at the molar activity deemed useful for clinical application, even at the two-week time point after end of chemical separation. DOTATOC, radiolabeled with either ¹⁶¹Tb or ¹⁷⁷Lu, was stable over 24 h in the presence of a stabilizer.

Conclusions: In this study, it was shown that ¹⁶¹Tb can be produced in high activities using different irradiation facilities. The developed method for ¹⁶¹Tb separation from the target material yielded ¹⁶¹TbCl₃ in quality suitable for high-specific radiolabeling, relevant for future clinical application.

Keywords: 161Tb; Auger/conversion electrons; DOTA; Purification method; Somatostatin analogues.

Fig. 1

Elution profile of ¹⁶¹Tb separation from the irradiated target material and side products (10 mm × 170 mm Sykam resin column, 8 mg ¹⁶⁰Gd₂O₃, 0.6 mL/min eluent flow rate)

Fig. 2

Schematic diagram of the ¹⁶¹Tb chemical separation system

Fig. 3

Gamma spectrum of ¹⁶¹Tb, obtained after the purification process. The radionuclidic impurity ¹⁶⁰Tb is not visible due to the negligible activity as compared to that of ¹⁶¹Tb at end of separation (EOS)

Fig. 4

HPLC chromatogram of ¹⁶¹Tb-DOTANOC (2.3 min retention time would indicate “free” or unlabeled ¹⁶¹Tb, while 8.2 min indicates ¹⁶¹Tb-DOTANOC)

Fig. 5

Comparison of the radiolabeling yield of (a) no-carrier-added ¹⁶¹Tb (SAFARI-1); b no-carrier-added ¹⁷⁷Lu (ITG) and (c) carrier-added ¹⁷⁷Lu (IDB) in combination with DOTA over time at different DOTA-to-nuclide molar ratios

Fig. 6

Stability of the radiopeptide over time, in the presence and absence of ascorbic acid: the graph shows the % intact ¹⁶¹Tb/¹⁷⁷Lu-DOTATOC over a period of 24 h. In the presence of ascorbic acid ¹⁷⁷Lu and ¹⁶¹Tb-DOTATOC curves overlap, making it impossible to visualize both simultaneously