^99mTc-Tricarbonyl Complexes Functionalized with Anthracenyl Fragments: Synthesis, Characterization, and Evaluation of Their Radiotoxic Effects in Murine Melanoma Cells

Abstract

Different pyrazolyl-diamine ligands bearing anthracenyl or anthrapyrazole functionalities as DNA-binding groups, at different positions of the chelator framework, were labeled with the fac-[(99m)Tc(CO)(3)](+) core. The resulting complexes, 1-4, are highly stable in vitro under physiologic conditions; all of them have been identified by high-performance liquid chromatography comparison with the Re congeners, with the exception of 3, that is anchored by an anthrapyrazole diamine ligand. Aiming to assess the ability of these complexes to target the cell nucleus and to induce enhanced cell death by effect of the Auger electrons emitted by (99m)Tc, the intracellular distribution and radiotoxicity of 1-4 were evaluated by using B16F1 murine melanoma cells. The radiotoxic effects depend very much on the position used to introduce the DNA-binding group and are well correlated with the nuclear uptake of the compounds. Complex 2, having the anthracenyl substituent at the 4-position of the pyrazolyl ring, rapidly entered the cells and accumulated inside the nucleus, exhibiting the highest radiotoxic effects. This compound induced an apoptotic cellular outcome, and its enhanced radiotoxic effects were certainly due to the Auger electrons emitted by the radiometal in close proximity to DNA.

Tricarbonyl M(I) (M = Re, 99mTc) complexes bearing acridine fluorophores: synthesis, characterization, DNA interaction studies and nuclear targeting

“…8 In our research group, we have also studied and evaluated Re(I)/ 99m Tc(I) tricarbonyl complexes anchored by pyrazolyl-diamine chelators and bearing anthracenyl groups for DNA binding. 10- 12 Our findings were encouraging since some of the anthracenyl-containing 99m Tc(I) tricarbonyl complexes rapidly entered the cells, accumulated inside the nucleus and exhibited a strong radiotoxic effect in murine melanoma cells with an apoptotic cellular outcome. However, the evaluated complexes only presented a moderate affinity to DNA and did not behave as perfect intercalators.…”

Molecular Assembly of Multifunctional 99mTc Radiopharmaceuticals Using “Clickable” Amino Acid Derivatives

“…Application of the latter to radiopharmaceuticals has been suggested for the delivery of short-range Auger-electron-emitting radioisotopes to the cell nucleus to enhance their therapeutic efficacy. [27,28] Finally, alkyne precursors 20 and 21 functionalized with an organic dye (DY547) or the macrocyclic chelator DOTA, respectively, represent examples of substrates for the development of dual-modality imaging agents. Conjugates derived from precursor 20 could be used for SPECT and optical (fluorescence) imaging whereas those obtained from DOTA derivative 21 would enable combination with other metals, such as paramagnetic gadolinium, yielding a potential MRI/SPECT probe.…”

Fluorous Iminoalditols: A New Family of Glycosidase Inhibitors and Pharmacological Chaperones

“…25 Derivatives 18 and 19 carry biotin, an affinity tag applicable for sequential bioconjugations (e.g., pre‐targeting approaches26) and acridine, a DNA intercalator, respectively. Application of the latter to radiopharmaceuticals has been suggested for the delivery of short‐range Auger‐electron‐emitting radioisotopes to the cell nucleus to enhance their therapeutic efficacy 27. 28 Finally, alkyne precursors 20 and 21 functionalized with an organic dye (DY547) or the macrocyclic chelator DOTA, respectively, represent examples of substrates for the development of dual‐modality imaging agents.…”