Diethylenetriaminetetrahydroxamic acid: A potential chelator for labeling antibody with Zr-89 for PET imaging

1187 Objectives Deferoxamine, the only clinically used chelator for labeling antibody with Zr-89, shows significant in vivo demetallation. One possible reason is that the three hydroxamate groups of deferoxamine are not enough to fulfill the octadentate requirement to stably complex Zr4+. Herein, we report the preparation and evaluation of DTTH-1, a diethylenetriaminetetrahydroxamic acid derivative, as a potential Zr-89 chelator for PET imaging. Methods For Zr-89 production, an yttrium disc, 10 mm diameter with 99.9% purity was bombarded with 13.9 MeV protons for 40 min (800 μA.min). The disc was dissolved and adjusted to 2M HCl and Zr-89 was extracted by hydroxamate resin. Zr-89 was eluted off the resin with 0.5 mL 1M oxalic acid. DTTH-1 was prepared via multi-step organic synthesis. Zr-89 complexation was performed at room temperature at pH 6, 7 and 8 (HEPES buffer, 0.5 M) with 200 µM DTTH-1, and at pH 7.5 with 20 µM DTTH-1 (equivalent to 0.4 mg antibody in 0.5 mL solution with on average 4 chelators/antibody). The complexation yield was determined 1 hour and 3 days later via ITLC developed using 50 mM EDTA buffer (pH 5). Results Zr-89 yield at the end of bombardment was 696 MBq of which 453 MBq was purifed and eluted in 0.5 mL 1M oxalic acid. DTTH-1 was prepared in an overall 4% yield. The Rfs of free Zr-89 and Zr-DTTH-1 complex were 1.0 and 0, respectively. Complexation of Zr-89 with 200 µM DTTH-1 at pH 7 and 8 was very efficient (>96% at 1 h), and the complexation yield remained relatively the same after 3 days (>92%). Complexation yield at pH 6 was 73% after 1 hour, and dropped to 33% 3 days later. Complexation yield with 20 µM DTTH-1 at pH 7.5 was 60% after 1 hour, and increased to 70 % 3 days later. Conclusions DTTH-1 showed high complexation yield with Zr-89 at pH 7 and 8 at both 1h and 3 day incubation. This pH is ideal for monoclonal antibody labeling. Further assessment is needed to compare in vivo stability of Zr-DTTH-1-antibody with Zr-desferroxiamine -antibody.

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