Synthesis and evaluation of fac-[99mTc/Re(CO)3]+ complexes with a new (N,S,N) bifunctional chelating agent: The first example of a fac-[Re(CO)3(N,S,N-sst2-ANT)] complex bearing a somatostatin receptor antagonist peptide

• Synthesis and characterization of a novel tridentate bifunctional fac-[99mTc/Re(CO)3(N,S,N)]+ chelate.
• High stability of a model bioconjugate complex [99mTc(CO)3(N,S,N)]+ in rat serum and rat urine.
• Synthesis of the first organometallic fac-[Re(CO)3]+ chelate conjugated to a somatostatin receptor antagonist peptide.

In this work, the synthesis of new fac-[99mTc/Re(CO)3(N,S,N)]+ complexes is presented with a novel tridentate bifunctional chelator, 3-(2-aminoethylthio)-3-(1H-imidazol-4-yl)propanoic acid (1), its pyrrolidine amide derivative (2), as well as with the 1-sst2-ANT bioconjugate amide (3), where the somatostatin receptor seeking peptide sst2-ANT [4-NO2-Phe-c(DCys-Tyr-DTrp-Lys-Thr-Cys)-DTyr-NH2] is linked to 1 via its N-terminus. The rhenium complexes of ligands 1, 2 and 3 (complexes 4, 5 and 6, respectively) were synthesized in high yield and were characterized spectroscopically. The fac-[Re(CO)3(N,S,N)]+ coordination mode of complexes 4 and 5 via the imidazole N, thioether S, and amine N donor atoms was determined by NMR. The 99mTc tracer complexes of ligands 1 and 2 (complexes 7 and 8, respectively) were synthesized quantitatively, and their identities were confirmed by HPLC co-elution with the Re analogues. In vitro stability studies of both 7 and 8 in histidine and cysteine showed that the complexes remained intact (>98%) after 24 h incubations. Furthermore, rat serum analysis of the small molecule bioconjugate model complex, 8, showed high stability at 4 h, and rat urine analysis showed that 8 was excreted intact through 4 h. Future studies with the sst2-ANT peptide linked to the fac-[99mTc(CO)3(N,S,N)]+ chelate will determine if targeted delivery of this attractive diagnostic radionuclide to neuroendocrine cancers that over-express somatostatin receptors can be achieved.

The synthesis and characterization of new fac-[99mTc/Re(CO)3(N,S,N)]+ complexes is presented with a new bifunctional chelator, 3-(2-aminoethylthio)-3-(1H-imidazol-4-yl)propanoic acid (1), its pyrrolidine derivative (2), and with the 1-sst2-ANT (3) bioconjugate, where sst2-ANT [4-NO2-Phe-c(DCys-Tyr-DTrp-Lys-Thr-Cys)-DTyr-NH2] is a somatostatin receptor seeking peptide. High stability of [99mTc(CO)3(1)]+ and [99mTc(CO)3(2)]+ was obtained in rat serum and urine analysis.Figure optionsDownload as PowerPoint slide