Technetium-99m complexes of l-arginine derivatives for targeting amino acid transporters. Issue 42 (14th June 2017)

• Record Type: Journal Article
• Authors: Morais, Maurício; Ferreira, Vera F. C.; Figueira, Flávio; Mendes, Filipa; Raposinho, Paula; Santos, Isabel; Oliveira, Bruno L.; Correia, João D. G.
• Is Part Of: Dalton transactions. Volume 46:Issue 42(2017)
• Page Start: 14537
• Page End: 14547
• Publication Date: 2017-06-14
• Subjects: Chemistry, Inorganic -- Periodicals; Chemistry, Physical and theoretical -- Periodicals; Chemistry, Inorganic -- Periodicals; 546.05
• DOI: 10.1039/c7dt01146f
• Languages: English
• ISSNs: 1477-9226

Abstract

Abstract : The metal complexTc2 exhibits relevant internalization in several cancer cell lines, likely to be mediated by cationic amino acid transporters. Abstract : Although relevant from the clinical point of view, radiotracers targeting cationic amino acid transporters are relatively unexplored and, in particular, no metal-based radiotracers are known. The rare examples of complexes recognized by amino acid transporters, namely by the Na + -independent neutrall -type amino acid transporter 1 (LAT1), are 99m Tc(i )/Re(i ) compounds. Herein, we describe conjugates comprising a pyrazolyl-diamine chelating unit and the cationic amino acidl -arginine (l -Arg) linked by a propyl (L 1 ) or hexyl linker (L 2 ), which allowed the preparation of stable complexes of the type fac -[ 99m Tc(CO)3 (k 3 -L)] + (Tc1, L =L 1 ;Tc2, L =L 2 ) and of the respective surrogatesRe1 andRe2 . Interestingly, complexTc2 exhibited moderate levels of time-dependent internalization in three human tumoural cell lines, with approximately 3% of total applied activity internalized, corresponding to 21% of the cell-associated activity. A putative mechanism of retention in the cytoplasm of cells could be the interaction of the complex with inducible nitric oxide synthase (iNOS), which is the enzyme responsible for the catalytic oxidation ofl -Arg to citrulline and nitric oxide. However, the surrogate complexRe2 does not recognize iNOS, as demonstrated by the in vitro assays with purified iNOS and in studies with lipopolysaccharide(LPS)-activated macrophages. Preliminary mechanistic studies suggest that the internalization ofTc2 is linked to the cationic amino acid transporters, namely system y + . This finding might open the way towards the development of novel families of metal-based radiotracers for probing metabolically active cancer cells.