A Novel Approach to the High-Specific-Activity Labeling of Small Peptides with the Technetium-99m Fragment [^99mTc(N)(PXP)]²⁺ (PXP = Diphosphine Ligand)

Abstract

A new labeling approach for incorporating bioactive peptides into a technetium-99m coordination complex is described. This method exploits the chemical properties of the novel metal-nitrido fragment [99mTc(N)(PXP)]2+, composed of a terminal Tc[triple bond] N multiple bond bound to an ancillary diphosphine ligand (PXP). It will be shown that this basic, molecular building block easily forms in solution as the dichloride derivative [99mTc(N)(PXP)Cl2], and that this latter complex selectively reacts with monoanionic and dianionic, bidentate ligands (YZ) having soft, pi-donor coordinating atoms to afford asymmetrical nitrido heterocomplexes of the type [99mTc(N)(PXP)(YZ)]0/+ without removal of the basic motif [99mTc(N)(PXP)]2+. The reactions of the amino acid cysteine was studied in detail. It was found that cysteine readily coordinates to the metal fragment [99mTc(N)(PXP)]2+ either through the [NH2, S-] pair of donor atoms or, alternatively, through the [O-, S-] pair, to yield the corresponding asymmetrical complexes in very high specific activity. Thus, these results were conveniently employed to devise a new, efficient procedure for labeling short peptide sequences having a terminal cysteine group available for coordination to the [99mTc(N)(PXP)]2+ fragment. Examples of the application of this novel approach to the labeling of the short peptide ligand H-Arg-Gly-Asp-Cys-OH (H(2)1) and of the peptidomimetic derivative H-Cys-Val-2-Nal-Met-OH (H2) will be discussed.

The Chemistry of Technetium–Water Complexes within the Manganese Triad: Challenges and Perspectives

“…Succinic dihydrazide was the nitrido source and SnCl 2 the reducing agent. [28][29][30] It should be noted at this point that the synthesis of nitrido complexes in the presence of b-type ligands always lead to Tc V and not to Tc VI compounds. [31] In a subsequent step the two chloride ligands were substituted by a biomolecule pendent ligand (a cysteine for instance), which led to the irreversible labelling of the targeting molecule.…”

Synthesis, Solution‐State and Solid‐State Structural Characterization of Monocationic Nitrido Heterocomplexes [M(N)(DTC)(PNP)]+ (M = 99Tc, Re; DTC = Dithiocarbamate; PNP = Heterodiphosphane)

“…[10,11] In the last few years, we have investigated the design of nitrido-containing species by exploiting the strong electrophilic character exhibited by the [M(N)(PNP)] 2ϩ metal fragment, which selectively reacts with nucleophilic bidentate ligands having a π-donor set of coordinating atoms. In particular, emphasis was placed on bidentate ligands containing both heteroatomic chelating sites (such as cysteine, thiocarboxylic acids, and aminothiols) and homoatomic sites (such as dithiols and dithiocarbamates).…”

“…For example, small peptides having a terminal cysteine residue have been efficiently labeled with the [ 99m Tc(N)(PNP)] 2ϩ complex at a high-specific-activity level. [10] A cysteine-conjugated 2-methoxyphenylpiperazine ligand was linked to the same metal fragment to investigate the binding affinity of the resulting heterocomplex for 5-HT 1A receptors in the central nervous system. [12] Within the class of homoatomic bidentate ligands, monoanionic dithiocarbamates (DTC) were found to possess a strong affinity for the [ 99m Tc(N)(PNP)] 2ϩ complex.…”

Synthesis, radiolabeling and evaluation of a new positively charged 99mTc‐labeled fatty acid derivative for myocardial imaging

“…Several reports are available in the literature on the synthesis and evaluation of 99m Tc-labeled fatty acid derivatives based on various metal cores albeit with suboptimal properties. [8][9][10][11][12][13][14][15][16][17][18] Among 21 core. The desired characteristics of a 99m Tc-labeled fatty acid are high uptake in the normal myocardium with retention long enough to carry out SPECT imaging and rapid clearance from background tissue/organs such as blood, liver and lungs.…”

“…Recently, a series of neutral and positively charged fatty acid derivatives labeled with [ 99m TcN(PNP)] 21 core have been prepared and evaluated in biological systems. 8 Our group working on similar complexes has earlier reported the synthesis and bio-evaluation of a neutral complex of a long chain 16-carbon fatty acid derivative.…”