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(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 [(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.

Cyclic‐RGD penta‐peptides cRGDyK derivatized with cyclopentadienyl complexes of technetium and rhenium as radiopharmaceutical probes

“…A previous study showed that small biomolecules can be conjugated to Thiele's acid to yield compounds of the form [(C 5 H 5 CONH‐R) 2 ] . Following this procedure, different linear tri‐peptide sequences such as Leu‐Gly‐Gly were coupled to (C 5 H 5 COOH) 2 .…”

“…The rhenium complexes [Re(η 5 ‐C 5 H 4 COOH)(CO) 3 ] can be obtained along different pathways . Originally, [M(η 5 ‐C 5 H 4 COOCH 3 )(CO) 3 ] (M═Re, Tc) was synthesized from [MO 4 ] − by the so‐called double ligand transfer reaction in the presence of CrCl 3 and a ferrocene (Fc) derivative that provides the Cp‐system.…”

“…Alternatively, reaction of NH 4 ReO 4 with [Re 2 (CO) 10 ] and Thiele's acid gave [M(η 5 ‐C 5 H 4 COOH)(CO) 3 ] . In a previous approach, [Re(η 5 ‐C 5 H 4 CONH‐R)(CO) 3 ] (R═tri‐peptides) were synthesized by conjugating [Re(η 5 ‐C 5 H 4 COOH)(CO) 3 ] to resin bound, protected tri‐peptides, followed by deprotection and cleavage from the resin …”

“…Thus, the cyclopentadienyl (Cp) ligand is an obvious choice because of its small size and low molecular weight. Notably, it mimics phenyl rings in pharmaceuticals or biomolecules such as amino acids and tripeptides . In extending ongoing research towards the labeling of biomolecules with [M(η 5 ‐C 5 H 4 ‐R)(CO) 3 ] (R═targeting group, M═ 99m Tc), the syntheses of a cyclic RGD peptide, radiolabeled by metal mediated retro Diels‐Alder reaction, was performed in an aqueous solution .…”

Formation, characterization and computational studies of mono- and dinuclear rhenium(I) chromone compounds

“…However, the next generation of potential rhenium radiopharmaceuticals requires chelators which can stabilize the metal centre both in the low and high oxidation states [7]. Furthermore, these multidentate chelators should also cater for the inclusion of biologically active moieties which may aid in the target specific biodistribution of the metallopharmaceuticals [8,9].…”