A new high-through-put in vivo screening method for the discovery of tissue targeting drug

Objective: To establish a model of totally random high-through-put in vivo screening for the discovery of tissue targeting drug. Methods: The C-terminal amide tripeptide libraries were synthesized on Rink Amide-4-methylbenzhydrylamine (MBHA) resin in the OXX→O1 OX→O1O2O[O represented one of the 20 natural L-amino acids in a defined position, O1-O2 represented a defined L-amino acid (after screening) in a defined position, and X represented a mixture of all the L-amino acids with the exception of Cys] positional scanning formal and iterative protocol. A technetium (V) oxo core [(TcO)3+] was bound to the N4-triligands of tripeptide libraries via four deprotonated amide nitrogen atoms to form a structure of 99Tcm-tripeptide libraries. The radio combinatorial screening in vivo was then carried out after SD rats and A549 tumor bearing mice injected with 99Tcm-tripeptide libraries. Results: Using 99Tcm-tripeptide libraries as an example, a new method of totally random high-through-put in vivo screening was demonstrated successfully in generation, optimization, and design of tissue targeting drugs. The uptake (%ID/g) of 99Tcm labeled drugs in their target tissues was highly structure dependent. Because the non-target tissue binding and the metabolism of 99Tcm-tripeptide libraries were simultaneously monitored successfully, the background activity was limited to the lowest level when a 99Tcm labeled drug finally generated. Conclusion: The random high-through-put in vivo screening method is sensitive and reliable for the discovery of tissue targeting drug. (authors)