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 [(η⁵-Cp(CONH-R))M(CO)₃] with M = Re or ^99mTc. The R group represents different tri-peptides (tpe) which display high binding affinities for oligopeptide transporters PEPT2. The ^99mTc complexes were prepared directly from [^99mTc(OH₂)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 [(η⁵-Cp)^99mTc(CO)₃] tag. We synthesized the Diels–Alder product [(HCpCONH-tpe)₂] from Thiele's acid [(η⁵-HCpCOOH)₂] via double peptide coupling. The Re-complexes [(η⁵-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 ^99mTc-complexes is confirmed by chromatographic comparison with the corresponding rhenium complexes, fully characterized by spectroscopic techniques.