Biotin Derivatives Carrying Two Chelating DOTA Units. Synthesis, in Vitro Evaluation of Biotinidases Resistance, Avidin Binding, and Radiolabeling Tests

The synthesis of four biotin derivatives carrying two DOTA moieties for each ligand (BisDOTA set) is reported, for increasing radiation/dose ratio and improving efficiency in the pretargeted avidin-biotin radioimmunotherapy. The biotin-containing scaffold of two BisDOTA was similar to the mono-DOTA derivative previously described. Then the scaffold was elongated by trifunctionalized spacers of different length and conjugated with one of the COOH groups of two DOTA. Two others were prepared starting from a on-resin lysine residue. The lysine alpha-NH2 was bonded to blotin, and then spacers were appended to the alpha-NH2 and conjugated with two DOTA molecules. One compound contairted a p-aminoberizoic acid spacer, which ensured higher head-to-tail distance and increased rigidity ofthe chain. These last two compounds had a very high ability to bond avidin and were labeled with Y-90 at high specific activity. All the compOLInds were resistant to the action of'scrurn biotinidases.