Impact of Different [99mtc][Tc(N)PNP]-Scaffolds on the Labeling of the Rgdfk Peptide and the Biological Properties of the Obtained Radiocompounds

An interesting platform to label biomolecules is the [99mTc][Tc(N)(PNP)]-system (PNP = bisphosphinoamine). Here we present a comparison of the reactivity of three different [Tc(N)(PNP)]-synthons, as well as their impact on the stability and biological properties of the corresponding [99mTc][Tc(N)(PNP)]-labeled RGDfK pentapeptide. Conjugation of the RGDfK with Cys was followed by labeling with the [99mTc][Tc(N)(PNP)]-synthons. Evaluation of the radiocompounds for their lipophilicity, stability and in vitro/in vivo targeting properties was then performed. All compounds were easily obtained in very high radiochemical yield (≥ 95%), but only the use of PNP3OH allows to obtain the corresponding [99mTc][Tc(N)(PNP3OH)(RGDfK)]+ at room temperature. The different synthons influence mainly the in vitro cell binding and in vivo performances of the radioconjugates. Different pharmacokinetics in healthy rats and tumor accumulation in mice xenofrafts were observed as a function of lipophilicity and sterical hindrance of the [99mTc][Tc(N)(PNP)]-framework. In particular [99mTc][Tc(N)(PNP3OH)(RGDfK)]+ and [99mTc][Tc(N)(PNP3)(RGDfK)]+ are better performing than the [99mTc][Tc(N)(PNP43)(RGDfK)]+; consequently, they are more suitable for further radiopharmaceutical purposes. In general, the good labeling properties of the less lipophilic and water soluble [99mTc][Tc(N)(PNP3OH)]– synthon are exploitable to the labeling of temperature-sensitive biomolecules.