Synthesis, characterization, and in vitro evaluation of new coordination complexes of platinum(ii) and rhenium(i) with a ligand targeting the translocator protein (TSPO)

Abstract

The 18 kDa translocator protein (TSPO) is overexpressed in many types of cancers and is also abundant in activated microglial cells occurring in inflammatory neurodegenerative diseases. The TSPO-selective ligand 2-(8-(2-(bis-(pyridin-2-yl-methyl)amino)acetamido)-2-(4-chlorophenyl)H-imidazo[1,2-a]pyridin-3-yl)-N,N-dipropylacetamide (CB256), which fulfills the requirements of a bifunctional chelate approach, has been used to synthesize coordination complexes containing either Pt (1) or Re (3), or both metal ions (2). The new metal complexes showed a cellular uptake markedly greater than that of the precursor metallic compounds and were also able to induce apoptosis in C6 glioma cells. The good cytotoxicity of the free ligand CB256 towards C6, A2780, and A2780cisR tumor cell lines was attenuated after coordination of the dipicolylamine moiety to Pt while coordination of the imidazopyridine residue to Re reduces the affinity towards TSPO. The results of the present investigation are essential for the design of new imidazopyridine bifunctional chelate ligands targeted to TSPO.

Synthesis and Evaluation of Tricarbonyl 99mTc-Labeled 2-(4-Chloro)phenyl-imidazo[1,2-a]pyridine Analogs as Novel SPECT Imaging Radiotracer for TSPO-Rich Cancer

“…The results show that the free TSPO ligand 3 has an appreciable affinity for TSPO (148 nM), which, however, is lower than that of the reference compound PK 11195 (9 nM). This result is in agreement with that previously reported [30], and the reduced affinity of compound 3 could be explained by the steric bulk generated by the dipicolylaminic moiety at position 8 of the imidazopyridine nucleus, which is crucial for the interaction of the ligand with mitochondrial TSPO [29,30]. As expected, compound 2 showed an affinity (159 nM) comparable to that of the free ligand (Table 1).…”

“…As expected, compound 2 showed an affinity (159 nM) comparable to that of the free ligand (Table 1). In fact, as already reported, the coordination of a metal ion (Pt(II)) to the tridentate bis-(2-picolyl)amine residue did not significantly alter the TSPO affinity of CB256, while metalation at the imidazopyridine moiety greatly reduced the affinity for TSPO [30]. Even though the affinity of compounds 2 and 3 are lower to that of the reference compound PK 11195, these binding values can be still good for biological applications.…”

“…The coordination potential of CB256 towards Pt(II) and Re(I) metal ions was already exploited by some of us and, in particular, two dinuclear Pt/Re and Re/Re complexes were prepared, indicating that the introduction of the di-(2-picolyl)amine moiety allows the coordination of a metal ion such as Pt 2+ or Re + [30]. Unlike our previous results of the dinuclear Re complex, only the homologous 99m Tc complex was generated in the radiolabeling reaction due to the low concentration of technetium.…”

“…In our previous studies, potent and selective imidazopyridine-based TSPO ligands—which could carry both a cytostatic platinum species and a rhenium complex as the precursor for introducing the 99m Tc-(CO) 3 unit—were reported [25,26,27,28,29,30]. Among the imidazopyridine-based TSPO ligands investigated so far, 2-(8-(2-(bis(pyridin-2-yl)methyl)amino)acetamido)-2-(4-chlorophenyl) H imidazo [1,2- a ] pyridin-3-yl)- N , N -dipropylacetamide (CB256, 3 ) contains the TSPO-targeting moiety and a metal ion anchor, namely di-(2-picolyl)amine, for a bifunctional chelate approach [29].…”

Bridging Pharmaceutical Chemistry with Drug and Nanoparticle Targeting to Investigate the Role of the 18‐kDa Translocator Protein TSPO

“…In this regard, Choi et al. recently prepared a novel 99m Tc‐tricarbonyl labelled imidazolpyridine compound useful for SPECT imaging of TSPO‐rich cancers using the 2‐(8‐(2‐(bis(pyridin‐2‐yl)methyl)amino)acetamido)‐2‐(4‐chlorophenyl)‐ H ‐imidazo[1,2‐ a ]pyridin‐3‐yl)‐ N , N ‐dipropylacetamide (CB256) as TSPO ligand, able to perform a bifunctional chelate approach, ( 1 , Figure ) . Some of us realized another rhenium complex to be used as a model of radiopharmaceutical agent targeted to TSPO obtained using the 2‐[6,8‐dichloro‐2‐(1,3‐thiazol‐2‐yl)‐ H ‐imidazo[1,2‐ a ]pyridin‐3‐yl]‐ N , N ‐di‐ n ‐propylacetamide (TZ6) as a potent and selective TSPO ligand ( 2 , Figure ).…”