Synthesis of tripeptide derivatized cyclopentadienyl complexes of Technetium and Rhenium as radiopharmaceutical probes

Abstract

We describe the syntheses of half-sandwich complexes of the type [(η$^5$-Cp(CONH-R))M(CO)$_3$] with M = Re or $^{99m}$Tc. The R group represents different tri-peptides (tpe) which display high binding affinities for oligopeptide transporters PEPT2. The $^{99m}$Tc complexes were prepared directly from [$^{99m}$Tc(OH$_2$)$_3$(CO)$_3$]+ and Diels–Alder dimerized, cyclopentadienyl derivatized peptides in water. This approach corroborates the feasibility of metal-mediated retro Diels–Alder reactions for the preparation of not only small molecules but also peptides carrying a [(η$^5$-Cp)$^{99m}$Tc(CO)$_3$] tag. We synthesized the Diels–Alder product [(HCpCONH-tpe)$_2$] from Thiele's acid [(η$^5$-HCpCOOH)$_2$] via double peptide coupling. The Re-complexes [(η$^5$-CpCONH-tpe)Re(CO)$_3$] were obtained by attaching [(Cp-COOH)Re(CO)$_3$] directly to the N-terminus of peptides as received from SPPS. The authenticity of the $^{99m}$Tc-complexes is confirmed by chromatographic comparison with the corresponding rhenium complexes, fully characterized by spectroscopic techniques.