Synthesis, characterization and biological evaluation of tricarbonyl M(i) (M = Re, 99mTc) complexes functionalized with melanin-binding pharmacophores

Abstract

Aiming to evaluate their potential as radioactive probes for in vivo targeting of melanotic melanoma and its metastases, we have synthesized 99m Tc(I) tricarbonyl complexes (Tc1-Tc8) anchored by pyrazolyl-containing chelators with (N 3 ) or (N 2 O) donor atom sets and functionalized with 2-aminoethyldiethylamine and 4-amino-N-(2-diethylaminoethyl)benzamide groups as melanin-binding pharmacophores. The chemical identification of the several 99m Tc complexes has been accomplished by HPLC comparison with the Re congeners (Re1-Re8), which were synthesized at the macroscopic level and fully characterized by common analytical techniques. The biological evaluation of the 99m Tc(I) complexes comprised the determination of their in vitro binding to synthetic melanin, measurement of cellular uptake in B16F1 murine melanoma cells, as well as biodistribution studies in B16F1 melanoma-bearing mice. All the tested complexes have shown a moderate to high in vitro affinity to melanin, with percentages of binding spanning between 60 and 94%. In agreement with the poor cellular uptake measured in vitro, the in vivo tumor uptake of the complexes was in general relatively low, ranging between 0.12 and 1.69% ID g À1 at 4 h p.i. However, some complexes have shown favorable tumor-to-organ ratios with values as high as 28 and 5.3 for tumor-muscle and tumor-blood ratios, respectively. This seems to indicate that some selectivity towards melanoma tissue was conserved, and encourages further optimization of the in vitro/in vivo biological properties of this type of complexes aimed at finding novel radioactive probes for non-invasive imaging of melanoma.

99mTcI/ReI Tricarbonyl Complexes with Tridentate Cysteamine Based Ligands: Synthesis, Characterization and in vitro/in vivo Evaluation

“…[15][16][17][18][19] In this field, our research group reported recently 99m Tc I tricarbonyl complexes of tridentate pyrazolyl containing chelators functionalized with N-(2-aminoethyl)diethylamine and 4-amino-N-(2-diethylaminoethyl)benzamide groups that act as melanin binders. [20] This class of complexes exhibited a high in vitro affinity for melanin but showed, in general, hydrophilic character, which certainly justified their poor uptake by murine melanoma cells. We anticipated that the framework of L 1 H will provide smaller and more lipophilic complexes than these previously reported complexes, while retaining affinity for melanin upon functionalization with a N-(dialkylaminoalkyl) pharmacophore.…”

“…Hence, we have evaluated the melanin affinity of 2a and 3a by incubation of the compounds with synthetic melanin in distilled water, and we have assessed the percentage of bound complexes that formed using a methodology described elsewhere. [20] The percentage of the complexes that bound to melanin was 23 and 31 % for 2a and 3a, respectively. Under the same conditions, complex 1a has shown negligible binding to melanin (less than 1 %), showing that the introduction of the N-diethylethylamine substituent contributes to an increase in the melanin affinity of the complexes.…”

Synthesis and Biological Studies of Pyrazolyl‐Diamine PtII Complexes Containing Polyaromatic DNA‐Binding Groups

“…As depicted in Scheme , the synthesis of L 2 and L 3 consisted of treatment either of 9‐(3‐aminopropyl)anthracene ( 1 ) or of 10‐(3‐aminopropyl)‐3,6‐bis(dimethylamino)acridinium ( 2 ) with an activated ester ( N ‐hydroxysuccinimide, NHS) of BOC‐protected pyrazolyl‐diamine derivative 3 . Compounds 1 and 3 were synthesized by the methods described in the literature11–15 and compound 2 was prepared from the commercially available acridine orange by the methodology that we had used previously for the butyric congener 10. After removal of the BOC protecting groups and appropriate workup, the final ligands L 2 and L 3 were recovered in moderate yields (40–65 %) as pale yellow and red solids, respectively.…”

“…All chemicals (analytical grade) were obtained from Aldrich, except for K 2 PtCl 4 , which was from Alfa Aesar (a Johnson Matthey Company, Karlsruhe, Germany), and used as received. The compounds L 1 Pt (L 1 = N 1 ‐(2‐(3,5‐dimethyl‐1 H ‐pyrazol‐1‐yl)ethyl)ethane‐1,2‐diamine),7 9‐(3‐aminopropyl)anthracene ( 1 )11–14 and tert ‐butyl N ‐(2‐(( tert ‐butoxy)carbonyl)(2‐(4‐(2‐(2,5‐dioxopyrrolidin‐1‐yl)‐2‐oxoethyl)‐3,5‐dimethylpyrazol‐1‐yl)ethyl)amino)ethyl)carbamate ( 3 )15 were prepared as reported elsewhere.…”

Pt(IV)/Re(I) Chitosan Conjugates as a Flexible Platform for the Transport of Therapeutic and/or Diagnostic Anticancer Agents

“…Indeed, the development of novel agents combining diagnostic and therapeutic (theranostic) tools has emerged as a new approach to fight cancer over the last decade [19,20]. Towards this goal, isostructural M(I) (M = 99m Tc or Re) tricarbonyl complexes have useful and unique features: (i) chemical robustness of the fac-[M(CO) 3 ] + core; (ii) well-studied coordination chemistry with a variety of chelating ligands including targeting molecules [21,22]; and, (iii) possible application in the design of metal-based cancer theranostic agents where Re complexes can be incorporated into a cytotoxic entity that will exert a therapeutic effect, while the 99m Tc congeners are part of the corresponding imaging tool for in vivo assessment of tumor accumulation. Furthermore, the Re(I) tricarbonyl complexes have also been recently explored as photosensitizers for photodynamic therapy (PDT) [23][24][25].…”