Synthesis of tripeptide derivatized cyclopentadienyl complexes of technetium and rhenium as radiopharmaceutical probes

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.