MULTIVALENT TUMOR-TARGETING WITH 1,3,5,7-TETRAKIS(AMINOMETHYL)ADAMANTANE USING BIOTIN AS A TARGETING DOMAIN
Brittany Ulloa, Carlos Gutierrez.
California State University Los Angeles, Los Angeles, CA.
We aim to test the notion that the biodistribution of MRI contrast agents can be influenced by the deliberate inclusion of modular targeting domains on these molecules. We have used the biotin-avidin ligand-receptor pair as a tumor-targeting domain in the development of these contrast agents, which also contain domains to complex the Gd(III) contrast agent and another to mediate the solubility of the complex in biological fluids. These domains have been attached to 1,3,5,7-tetrakis(aminomethyl)adamantane, a symmetrical tetrahedral polyamine. This has been achieved through selective acylation of the polyammonium conjugate acid, in effect using protons as protecting groups. We have designed a C3V-targeting motif based on the tetrahedral 1,3,5,7-tetrakis(aminomethyl)adamantine. Three of the equivalent amine groups are selectively acylated with biotin; the fourth remains for conjugation to the diagnostic agent. Here, we describe work on the synthesis of this targeting domain. Adamantane was brominated to 1,3,5,7-tetrabromoadamantane, which was converted to 1,3,5,7-tetracyanoadamantane by a photochemical free radical nucleophilic substitution. The tetranitrile was reduced to yield the core 1,3,5,7-tetrakis(aminomethyl)adamantane, which was isolated as the tetra(hydrochloride) salt. We have developed chemistry for the selective acylation of this core to produce the tri(biotin) targeting domain. Future work will include the incorporation into MRI components for tracking of these molecules in vivo.