Mono‐, bi‐, or tridentate ligands? The labeling of peptides with ^99mTc‐carbonyls

Abstract

The labeling of targeting peptides with (99m)Tc is a useful concept for the diagnosis of various diseases such as cancer. Although in research for at least one decade, only a very few radiopharmaceuticals based on peptides are in clinical use. The difficulty of labeling, and the resulting authenticity of the new vector, is largely responsible for this observation. In this overview, we present an alternate strategy based on the organometallic fac-[(99m)Tc(CO)(3)](+) core for introducing (99m)Tc in biomolecules in general and in peptides in particular. The three coordination sites available in [(99m)Tc(OH(2))(3)(CO)(3)](+) can be occupied with many different ligand types, pendant to a biomolecule and serving as the anchor group for labeling. This makes the appropriate choice difficult. We intend to present some useful concepts for the practice. Monodentate chelators are robust but bear the risk of multiple binding of biomolecules. Coordinating a bidentate ligand of choice prior to labeling bypasses this problem and enables a systematic drug discovery by variation of the bidentate ligand. Bidentate ligands attached to the biomolecule are stronger but occasionally require protection of the remaining site by a monodentate ligand. Both approaches refer to a mixed-ligand [2+1] approach. Tridentate chelators are the most efficient but need some protecting group chemistry in order to achieve selectivity for the coupling process. Examples with cysteine and histidine are presented. This article aims to provide versatile and reproducible approaches for the labeling of biomolecules while not focusing on particular systems. It should be left to the readers to derive a strategy for their own peptide.

Synthesis and Characterisation of [Re(CO)3(SS)(P)] Complexes: A [2+1] Concept for 99mTc‐ and 188Re‐Radiopharmaceutical Applications

“…Nevertheless, tricoordination can also be achieved by using a mixture of two ligands, one bidentate L 2 and one monodentate L 1 to produce an [M(L 2 )(L 1 -Biomol)(CO) 3 ] complex by means of a [2+1] mixed-ligand approach (Scheme 1). [8] A recent paper has reported the use of this "[2+1]" approach to prepare new fac-M(CO) 3 compounds for radiopharmaceutical use from a dithiocarbamate and a monodentate isocyanide ligand.…”

Functionalised Tris(pyrazolyl)methane Ligands and Re(CO)3 Complexes Thereof

“…[1][2][3] Several groups are developing ligands for the radio-labelling of bio-molecules. [4][5][6][7][8][9][10][11][12][13][14][15][16][17][18] Many of these ligating moieties are based upon bis(pyridylmethyl)amine derivatives and we have also developed a N-(2-hydroxypropyl)methacrylamide (HPMA) copolymer with bis(pyridylmethyl)amine derivatives as metal binding sites. [19] Another class of widely used ligands in coordination chemistry and organometallic chemistry are the tris(pyrazolyl)borates (Tp), developed by Trofimenko in the early sixties.…”

Vitamin B12–Metal Conjugates for Targeted Chemotherapy and Diagnosis: Current Status and Future Prospects

“…[59][60][61] Owing to the low-spin d 6 electronic configuration of technetium(I), the resulting complexes possess great robustness in water, especially towards oxidation or carbonyl ligand substitution. -and, given the small size of the metal core, labeling of biomolecules can be achieved with retention of activity and specificity.…”

“…[61] Therefore, pen- dant groups of biomolecules such as the peripheral propionamide side chains of the cobalamin corrin ring may serve as anchor sites for labeling once appropriately derivatized. Over the past decade, the so-called single amino acid chelate (SAAC) strategy has been introduced as a new approach for the preparation of labeled amino acid containing bioconjugates.…”