Radiochemistry and biological evaluation of novel 2-hydroxyisophthalamide and 3-hydroxy-2-oxopyridine ligands as chelators for ⁸⁹Zr

Objectives ⁸⁹Zr-desferrioxamine (DFO) complexes are widely used in immunoPET applications despite recent observations suggesting instability of the radiometal chelate in vivo. These observations have stimulated interest in the development of new chelators that would form ⁸⁹Zr-complexes that are more stable in vivo. This report describes the synthesis, radiochemistry and biological evaluation of novel 2-hydroxyisophthalamide (IAM) and 3-hydroxy-2-oxopyridine (HOPO) ligands (A and B) as chelators for ⁸⁹Zr.

Methods All ligands were synthesized using novel, high dilution procedures. These ligands were radiolabeled with ⁸⁹Zr with purity and reaction progress monitored by radio-TLC and radio-HPLC. Stability of each complex was evaluated in PBS, 50 mM DTPA and human serum and compared with ⁸⁹Zr-DFO. Lipophilicty (LogP) values using a water:octanol partition were also determined.

Results Formation of the ⁸⁹Zr-HOPO complexes was complete and quantitative after 30 minutes at room temperature, but the formation of ⁸⁹Zr-IAM required more rigorous reaction conditions. After seven days, transchelation was observed in all complexes with the relative order of stability to DTPA challenge being ⁸⁹Zr-HOPO-A>⁸⁹Zr-HOPO-B>⁸⁹Zr-DFO > ⁸⁹Zr-IAM. In addition, the⁸⁹Zr-IAM and ⁸⁹Zr-HOPO complexes were observed to be more lipophilic than ⁸⁹Zr-DFO [(⁸⁹Zr-IAM vs. ⁸⁹Zr-HOPO-A vs. ⁸⁹Zr-HOPO-B vs. ⁸⁹Zr-DFO): -2.65±0.03 vs. -1.53 ±0.04 vs. -1.58 ±0.02 vs. -2.68±0.04].

Conclusions Both ⁸⁹Zr-HOPO complexes demonstrated greater lipophilicity and greater stability against DTPA challenge when compared with ⁸⁹Zr-DFO while ⁸⁹Zr-IAM demonstrated comparable lipophilicity and was less stable to DTPA challenge. The results of comparative biodistribution studies with ⁸⁹Zr-DFO will be highlighted, and the utility of these novel ligands as ⁸⁹Zr chelators will be discussed.

Research Support This work was supported by Wake Forest Health Sciences.