Plasma stability and pharmacokinetics of radiolabeled deferoxamine-biotin derivatives.

The extraordinary high affinity of biotin for streptavidin may be exploited in a two-step in vivo approach for delivering radiolabeled biotin derivatives suitable for imaging and therapy to lesion-bound streptavidin-conjugated monoclonal antibodies. Compared to the use of directly radiolabeled monoclonal antibodies, the two-step approach is desirable because of the fast renal clearance of radiobiotin, which reduces in vivo background levels and radiation dose. Deferoxamine binds with high-affinity trivalent metals useful for imaging and radiotherapy. Three deferoxaminebiotin derivatives were synthesized, radiolabeled and their stabilities tested in vitro in dog plasma and in vivo in the dog by an avidin binding assay and high-performance liquid chromatography. Defero-desaminolysyl-biotin (DLB) was unstable, with immediate degradation evident. A plasma enzyme, biotinidase, converts biocytin to biotin. DLB closely resembles biocytin, and analysis of the urine and plasma suggested rapid degradation of DLB to biotin and desaminolsyl-deferoxamine. Defero-biotin, a direct conjugate of deferoxamine and biotin, was similarly tested and found to be more stable. Defero-acetyl-cysteinyl-biotin contains a carboxyl group adjacent to the amide bond cleavage site of biotinidase. In vitro at 24 hr in plasma, defero-acetyl-cysteinyl-biotin was 87% stable, compared to 45% and 15% for defero-biotin and DLB, respectively. The pharmacokinetics of the three derivatives were similar, with 80% of the injected doses found in the urine at 6 hr; however, only defero-acetyl-cysteinyl-biotin was present as the intact moiety.