Biotin reagents in antibody pretargeting.: 6.: Synthesis and in vivo evaluation of astatinated and radioiodinated aryl- and nido-carboranyl-biotin derivatives

An investigation has been conducted to prepare and evaluate several radiohalogenated biotin derivatives as part of our studies to develop reagents for carrying At-211 in cancer pretargeting protocols. The primary goal of the investigation was to determine the in vivo stability and distribution properties of astatinated biotin derivatives. In addition to astatination, the biotin derivatives were radioiodinated for in vitro and in vivo comparison. Biodistributions were conducted in athymic mice, with sacrifice times of 1, 4, and 24 h to correspond to 9%, 32%, and 90% of At-211 decay (t(1/2) = 7.21 h). In the investigation, two biotin derivatives, 1a and 2a, were synthesized which had structures that contain a biotin moiety, a biotinidase-blocking moiety, an ether linker moiety, and an aryl stannane moiety for radiohalogenation. Biotin derivatives la and 2a were radiolabeled with I-125/131 to give [I-125/131] 1b or [I-125]2b and with At-211 to give [At-211]1c or [At-211]2c. In vivo studies demonstrated that co-injected [I-125]2b, and [I-131]1b had very similar tissue distributions in athymic mice. Co-injection of [At-211]2c and [I-125]2b provided data that indicated that rapid deastatination occurred in vivo. A second set of biotin derivatives, 3a, 4a, and 5a, were synthesized which had structures that contain a biotin moiety, a biotinidase-blocking moiety, and an anionic nido-carborane moiety for radiohalogenation. The biotin derivatives 4a and 5a contained an aryl moiety not present in 3a, and 5a had a trialkylamine functionality not present in 3a or 4a. Biotin derivative 3a was radioiodinated, but was not further investigated. Biotin derivatives 4a and 5a were radiolabeled with At-211 and I-125 to produce [I-125]4b/[At-211]4c and [I-125]5b/[At-211]5c. Comparison of [I-125]4b and (separately) [I-125]5b with [I-131]1b showed that the nido-carborane containing biotin derivatives were retained in blood and tissue more than the aryl iodide derivative. In vivo evaluations of [At-211]4c/[I-125]4b and (separately) [At-211]5C/[I-125]5b indicated that some deastatination occurred in these compounds, but it was much less than observed for the aryl derivative [At-211]2c. While the nido-carborane containing biotin derivatives provide a significant improvement in astatine stability over biotin derivatives previously studied, additional derivatives need to be prepared and studied to further improve the in vivo stability and blood/tissue clearance of these compounds.