Preparation, 99mTc-labeling and biodistribution studies of a PNA oligomer containing a new ligand derivative of 2,2'-dipicolylamine

Abstract

A new azido derivative of 2,2'-dipicolylamine (Dpa), 2-azido-N,N-bis((pyridin-2-yl)methyl)ethanamine, (Dpa-N(3)) was readily prepared from the known 2-(bis(pyridin-2-ylmethyl)amino)ethanol (Dpa-OH). It was demonstrated that Dpa-N(3) could be efficiently labeled with both [Re(CO)(3)(H(2)O)(3)]Br and [(99m)Tc(H(2)O)(3)(CO)(3)](+) to give [Re(CO)(3)(Dpa-N(3))]Br and [(99m)Tc(CO)(3)(Dpa-N(3))](+), respectively. Furthermore, Dpa-N(3) was successfully coupled, on the solid phase, to a Peptide Nucleic Acid (PNA) oligomer (H-4-pentynoic acid-spacer-spacer-tgca-tgca-tgca-Lys-NH(2); spacer= -NH-(CH(2))(2)-O-(CH(2))(2)-O-CH(2)-CO-) using the Cu(I)-catalyzed [2+3] azide/alkyne cycloaddition (Cu-AAC, often referred to as the prototypical "click" reaction) to give the Dpa-PNA oligomer. Subsequent labeling of Dpa-PNA with [(99m)Tc(H(2)O)(3)(CO)(3)](+) afforded [(99m)Tc(CO)(3)(Dpa-PNA)] in radiochemical yields >90%. Partitioning experiments in a 1-octanol/water system were carried out to get more insight on the lipophilicity of [(99m)Tc(CO)(3)(Dpa-N(3))](+) and [(99m)Tc(CO)(3)(Dpa-PNA)]. Both compounds were found rather hydrophilic (log D(o/w) values at pH=7.4 are -0.50: [(99m)Tc(CO)(3)(Dpa-N(3))](+) and -0.85: [(99m)Tc(CO)(3)(Dpa-PNA)]. Biodistribution studies of [(99m)Tc(CO)(3)(Dpa-PNA)] in Wistar rats showed a very fast blood clearance (0.26 ± 0.1 SUV, 1h p.i.) and modest accumulation in the kidneys (5.45 ± 0.45 SUV, 1h p.i.). There was no significant activity in the thyroid and the stomach, demonstrating a high in vivo stability of the (99m)Tc-labeled Dpa-PNA conjugate.