Synthesis and ^99mTc-Labeling of a PNA Oligomer Containing a New Ligand Derivative of 2,2´-Dipicolylamine

The search for chelating ligands which can be efficiently labeled with radiometals, and which also contain a functional group allowing a facile conjugation to biomolecules is currently a hot topic in radiopharmacy. The 2,2’-dipicolylamine (Dpa) has already been found to be a good candidate for labeling with ¹⁸⁶Re, ¹⁸⁸Re and ^99mTc¹ while the Cu(I)-catalyzed [2+3] azide/alkyne cycloaddition, often referred to as Click Chemistry,² has been shown to be an effective coupling method. With this in mind, we recently developed the facile synthesis of an azido derivative of Dpa (Dpa-N₃, Figure 1).³ Furthermore, as a proof of principle of the possible functionalization of our ligand to a biomolecule, Dpa-N₃ was successfully coupled, on the solid phase, to a ethinyl-substituted Peptide Nucleic Acid (PNA) oligomer employing the Click Chemistry methodology to give the expected Dpa-ethyl-triazol-PNA. Both Dpa-N₃ and Dpa-ethyl-triazol-PNA could be efficiently labeled with ^99mTc using the precursor [^99mTc(H₂O)₃(CO)₃]⁺ to afford [^99mTc(CO)₃(Dpa-ethyl-triazol-N₃)]⁺ and [^99mTc(CO)₃(Dpa-ethyl-triazol-PNA], respectively. The radionuclide ^99mTc was tightly bound by the Dpa-chelator avoiding the formation of pertechnetate for at least 24h. Partitioning experiments in a 1-octanol/water system confirmed that both [^99mTc(CO)₃(Dpa-N₃)]⁺ and [^99mTc(CO)₃(Dpa-ethyl-triazol-PNA] are rather hydrophilic. Biodistribution studies of [^99mTc(CO)₃(Dpa-ethyl-triazol-PNA] in Wistar rats showed a fast blood clearance and only a modest accumulation in the kidneys. Similar results were found when a mouse model (NMRI nu/nu) was used.

References

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3. G. Gasser, K. Jäger, M. Zenker, R.Bergmann, J. Steinbach, H. Stephan, N. Metzler-Nolte, 2010, submitted.