title: 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.
authors.affiliation: Forschungszentrum Dresden-Rossendorf, Institute of Radiopharmacy, PF 510119, D-01314 Dresden, Germany. gilles.gasser@aci.uzh.ch
authors.forename: Gilles
authors.initials: G
authors.lastname: Gasser
authors.forename: Katrin
authors.initials: K
authors.lastname: Jäger
authors.forename: Martin
authors.initials: M
authors.lastname: Zenker
authors.forename: Ralf
authors.initials: R
authors.lastname: Bergmann
authors.forename: Jörg
authors.initials: J
authors.lastname: Steinbach
authors.forename: Holger
authors.initials: H
authors.lastname: Stephan
authors.forename: Nils
authors.initials: N
authors.lastname: Metzler-Nolte
mesh_terms: D020003:1-Octanol / Q000737:chemistry; D000588:Amines / Q000737:chemistry*; D000818:Animals; D004247:DNA / Q000737:chemistry; D004355:Drug Stability; D006863:Hydrogen-Ion Concentration; D007553:Isotope Labeling; D007668:Kidney / Q000378:metabolism; D008024:Ligands; D008297:Male; D008657:Metabolic Clearance Rate; D008958:Models, Molecular; D015609:Organotechnetium Compounds / Q000138:chemical synthesis* / Q000737:chemistry / Q000493:pharmacokinetics*; D020135:Peptide Nucleic Acids / Q000138:chemical synthesis* / Q000737:chemistry / Q000493:pharmacokinetics*; D010848:Picolinic Acids / Q000737:chemistry*; D011897:Random Allocation; D051381:Rats; D017208:Rats, Wistar; D012015:Reference Standards; D012211:Rhenium / Q000737:chemistry; D012995:Solubility; D013667:Technetium; D014018:Tissue Distribution; D014867:Water / Q000737:chemistry
chemical_list: C501847:2,2'-dipicolylamine; D000588:Amines; D008024:Ligands; D015609:Organotechnetium Compounds; D020135:Peptide Nucleic Acids; D010848:Picolinic Acids; D014867:Water; D012211:Rhenium; D013667:Technetium; D004247:DNA; D020003:1-Octanol