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Technetium-99m complexes of l-arginine derivatives for targeting amino acid transportersElectronic supplementary information (ESI) available. See DOI: 10.1039/c7dt01146f
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 neutra...
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| Main Authors: | , , , , , , , |
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| Format: | Article |
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| Summary: | 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 neutral
l
-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 acid
l
-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 surrogates
Re1
and
Re2
. Interestingly, complex
Tc2
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 of
l
-Arg to citrulline and nitric oxide. However, the surrogate complex
Re2
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 of
Tc2
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.
The metal complex
Tc2
exhibits relevant internalization in several cancer cell lines, likely to be mediated by cationic amino acid transporters. |
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| ISSN: | 1477-9226 1477-9234 |
| DOI: | 10.1039/c7dt01146f |