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Background: Sc/Sc is an attractive theranostic pair for targeted in vivo positron emission tomographic (PET) imaging and beta-particle treatment of cancer. The Ti/Sc generator allows daily onsite production of this diagnostic isotope, which may provide an attractive alternative for PET facilities that lack in-house irradiation capabilities. Early animal and patient studies have demonstrated the utility of Sc. In our current study, we built and evaluated a novel clinical-scale Ti/Sc generator, explored the pharmacokinetic profiles of ScCl, [Sc]-citrate and [Sc]-NODAGA (1,4,7-triazacyclononane,1-glutaric acid-4,7-acetic acid) in naïve mice, and estimated the radiation burden of ScCl in humans.
Methods: Ti/Sc (101.2 MBq) in 6 M HCl solution was utilized to assemble a modular ZR resin containing generator. After assembly, Sc was eluted with 0.05 M HCl for further PET imaging and biodistribution studies in female Swiss Webster mice. Based on the biodistribution data, absorbed doses of ScCl in human adults were calculated for 18 organs and tissues using the IDAC-Dose software.
Results: Ti in 6 M HCl was loaded onto the organic resin generator with a yield of 99.97%. After loading and initial stabilization, ScCl was eluted with 0.05 M HCl in typical yields of 82.9 ± 5.3% (N = 16), which was normalized to the estimated generator capacity. Estimated generator capacity was computed based on elution time interval and the total amount of Ti loaded on the generator. Run in forward and reverse directions, the Sc/Ti ratio from a primary column was significantly improved from 1038 ± 440 to 3557 ± 680 (Bq/Bq) when a secondary, replaceable, ZR resin cartridge was employed at the flow outlet. In vivo imaging and ex vivo distribution studies of the reversible modular generator for ScCl, [Sc]-citrate and [Sc]-NODAGA show that free Sc remained in the circulation significantly longer than the chelated Sc. The dose estimation of ScCl reveals that the radiation burden is 0.146 mSv/MBq for a 70 kg adult male and 0.179 mSv/MBq for a 57 kg adult female. Liver, spleen and heart wall will receive the highest absorbed dose: 0.524, 0.502, and 0.303 mGy/MBq, respectively, for the adult male.
Conclusions: A clinical-scale Ti/Sc generator system with a modular design was developed to supply ScCl in 0.05 M HCl, which is suitable for further radiolabeling and in vivo use. Our data demonstrated that free ScCl remained in the circulation for extended periods, which resulted in approximately 10 times greater radiation burden than stably chelated Sc. Stable Sc/Sc-complexation will be more favorable for in vivo use and for clinical utility.
