Abstract

Anew 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)(H2O)(3)]Br and Tc-99m(H2O)(3)(CO)(3)] to give Re(CO)(3)(Dpa-N-3)]Br and Tc-99m(CO)(3)(Dpa-N-3)](+), respectively. Furthermore, Dpa-N3 was successfully coupled, on the solid phase, to a Peptide Nucleic Acid (PNA) oligomer (H-4-pentynoic acid-spacer-spacer-tgca-tgca-tgca-Lys-NH2; spacer = -NH-(CH2)(2)-O-(CH2)(2)-O-CH2-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 Tc-99m(H2O)(3)(CO)(3)](+) afforded Tc-99m(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 Tc-99m(CO)(3)(Dpa-N-3)(+) and Tc-99m(CO)(3)(Dpa-PNA)]. Both compounds were found rather hydrophilic (log D-o/w values at pH = 7.4 are -0.50: Tc-99m(CO)(3)(Dpa-N-3)](+) and 0.85: Tc-99m(CO)(3)(Dpa-PNA)]. Biodistribution studies of Tc-99m(CO)(3)(Dpa-PNA)] in Wistar rats showed a very fast blood clearance (0.26 +/- 0.1 SUV, 1 h p.i.) and modest accumulation in the kidneys (5.45 +/- 0.45 SUV, 1 h p.i.). There was no significant activity in the thyroid and the stomach, demonstrating a high in vivo stability of the Tc-99m-labeled Dpa-PNA conjugate. (C) 2010 Elsevier Inc. All rights reserved.