Peptide Targeted Radiopharmaceuticals

Oligopeptides have been actively investigated as vectors for targeting radio-nuclides to specific receptor systems. For example, 111In-labeled Octreotide, which is a somatostatin analogue, is used clinically to image neuroendocrine tumors.62 There have been a substantial number of peptides that have been labeled with Tc using both tetradentate NxS(4_x) and HYNIC-type ligands. These include compounds targeted at the formyl peptide receptor for imaging sites of infection and inflammation and bombesin receptors for tumor imaging. Reviews of peptide-Tc conjugates can be found throughout the literature.63 66

Because different amino acid residues can bind technetium, it is essential that the structure of Tc-peptide complexes that are being evaluated as novel radio-pharmaceuticals be determined unambiguously. Although this would be best done by X-ray crystallography, the majority of 99Tc-labeled peptides do not form single crystals. As a result, multi-NMR spectroscopy has proven to be a very useful tool for studying the structure of 99Tc-peptide derivatives.

A recent example of the work involved in characterizing a peptide-based metalloradiopharmaceutical was reported by Francesconi and co-workers.67 [99mTcO] apcitide is a cyclic peptide derivative that is designed to target the GPllb/llla receptor, which is expressed on activated platelets, as a means of imaging deep vein thrombosis in the lower extremities. The peptide as a bis-succinimidomethyl ether-linked dimmer is available as a kit (trade name AcuTect) and is approved for clinical use in the United States.

The peptide is engineered in such a manner that the metal is designed to bind to the three deprotonated amides and thiol of the Gly11-Gly12-Cys13-binding motif (an N3S ligand). The product produced by labeling the peptide with macroscopic amounts of 99Tc (using TcOCl^) showed similar retention time to the product produced at the tracer level. NMR studies of [99TcO] apcitide, following HPLC purification, in H2O/D2O mixtures showed the loss of the amide protons associated with coordination of Tc to the deprotonated nitrogen atoms of the Gly-Gly-Cys sequence. This was accompanied by changes in the chemical shift and splitting patterns of the a-methylene protons of the glycine amino acids and the a-methine proton of the cysteine CH group. These shifts, which are similar to those reported for simpler but analogous N3S chelates, support the belief that the metal binds to the target sequence. It should also be noted that infrared spectroscopy confirmed that the complex contains, as would be expected, the {TcO}3+ core. The Tc=O stretching vibration in Tc(V) coordination complexes is characteristic and typically appears between 890 and 1020 cm-1.

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