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

A new azido derivative of 2,2′-dipicolylamine (Dpa), 2-azido-N,N-bis((pyridin-2-yl)methyl)ethanamine, (Dpa-N3) was readily prepared from the known 2-(bis(pyridin-2-ylmethyl)amino)ethanol (Dpa-OH). It was demonstrated that Dpa-N3 could be efficiently labeled with both [Re(CO)3(H2O)3]Br and [99mTc(H2O)3(CO)3]+ to give [Re(CO)3(Dpa-N3)]Br and [99mTc(CO)3(Dpa-N3)]+, 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 [99mTc(H2O)3(CO)3]+ afforded [99mTc(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 [99mTc(CO)3(Dpa-N3)]+ and [99mTc(CO)3(Dpa-PNA)]. Both compounds were found rather hydrophilic (log Do/w values at pH = 7.4 are −0.50: [99mTc(CO)3(Dpa-N3)]+ and −0.85: [99mTc(CO)3(Dpa-PNA)]. Biodistribution studies of [99mTc(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 99mTc-labeled Dpa-PNA conjugate.

A new azido derivative of 2,2′-dipicolylamine (Dpa) was readily prepared and coupled to a PNA oligomer by solid phase synthesis. After radiolabeling with the 99mTc(CO)3 fragment, this conjugate was used for radiolabeling studies in mice.Figure optionsDownload as PowerPoint slide