Preclinical in vivo application of 152Tb-DOTANOC: a radiolanthanide for PET imaging

Cristina Müller, Christiaan Vermeulen, Karl Johnston, Ulli Köster, Raffaella Schmid, Andreas Türler, Nicholas P. van der Meulen

Terbium has attracted the attention of researchers and physicians due to the existence of four medically interesting radionuclides, potentially useful for SPECT and PET imaging, as well as for α- and β(-)-radionuclide therapy. The aim of this study was to produce (152)Tb (T 1/2 = 17.5 h, Eβ+av = 1140 keV) and evaluate it in a preclinical setting in order to demonstrate its potential for PET imaging. For this purpose, DOTANOC was used for targeting the somatostatin receptor in AR42J tumor-bearing mice. (152)Tb was produced by proton-induced spallation of tantalum targets, followed by an online isotope separation process at ISOLDE/CERN. After separation of (152)Tb using cation exchange chromatography, it was directly employed for radiolabeling of DOTANOC. PET/CT scans were performed with AR42J tumor-bearing mice at different time points after injection of (152)Tb-DOTANOC which was applied at variable molar peptide amounts. (177)Lu-DOTANOC was prepared and used in biodistribution and SPECT/CT imaging studies for comparison with the PET results. After purification, (152)Tb was obtained at activities up to ~600 MBq. Radiolabeling of DOTANOC was achieved at a specific activity of 10 MBq/nmol with a radiochemical purity >98 %. The PET/CT scans of mice allowed visualization of AR42J tumor xenografts and the kidneys, in which the radiopeptide was accumulated. After injection of large peptide amounts, the tumor uptake was reduced as compared to the result after injection of small peptide amounts. PET images of mice, which received (152)Tb-DOTANOC at small peptide amounts, revealed the best tumor-to-kidney ratios. The data obtained with (177)Lu-DOTANOC in biodistribution and SPECT/CT imaging studies confirmed the (152)Tb-based PET results. Production of 30-fold higher quantities of (152)Tb as compared to the previously performed pilot study was feasible. This allowed, for the first time, labeling of a peptide at a reasonable specific activity and subsequent application for in vivo PET imaging. As a β(+)-particle-emitting radiolanthanide, (152)Tb would be of distinct value for clinical application, as it may allow exact prediction of the tissue distribution of therapeutic radiolanthanides.