Summary:
The aim of the present study is the synthesis and characterization of new
rhenium(I) and technetium-99m(I) mixed ligand complexes with specialized
activity in melanoma. The complexes follow the general form fac-[Μ(CO)3L(Χ)],
were Μ=Re or 99mTc, LH is the bidentate monoanic ligand
3-(2-(diethylaminoethylaminocarbonyl) pyrazine-2-carboxylic acid and X a
monodentate ligand (imidazole (im), cycloexyl isocyanide (isc) or
triphenylpsosphine (PPh3)). The bidentate ligand was composed to bear the NO
system that stabilizes the fac-[Μ(CO)3]+ (were Μ=Re or 99mTc) core and also to
have structural similarities with N-(2-diethylaminoethyl) benzamide (ΒΖΑ) which
is considered to be the appropriate biological vector for melanoma. The
key-compound of this synthesis is the 2,3-pyrazinecarboxylic anhydride. It
reacts readily with 2-diethylaminoethyl amine generating the LH ligand. Then,
the [ΝΕt4]2[ReBr3(CO)3] precursor reacts with equimolar quantity of LH
producing the fac-[Re(CO)3(L)(H2O)], 1, complex. 1 can react consequently with
imidazole (im), cycloexyl isocyanide (isc) or triphenylpsosphine (PPh3),
resulting the complexes fac-[Re(CO)3(L)(im)], 2, fac-[Re(CO)3(L)(isc)], 3, and
fac-[Re(CO)3(L)(PPh3)], 4. Prolonged reaction of 4 with PPh3 leads to complex
trans-[Re(CO)2(L)(PPh3)2], 5. Complex 5 can also be synthesized with excess of
PPh3 at the reaction of 1 or reaction of LH with mer-[ReCl(CΟ)3(PPh3)2]. All
rhenium complexes were characterized by IR, NMR spectroscopies and elemental
analysis. The structure of complex 5 was elucidated by X-ray crystallography.
The preparation of the analogous 99mTc complexes was obtained by adding the
bidentate ligand LH to the fac-[99mTc(CO)3(H2O)3]+ precursor resulting to the
fac-[99mΤc(CO)3(L)(Η2Ο)], 1΄, complex in high radiochemical yield. Addition of
imidazole to complex 1΄ in room temperature for 20 min leads to a mixture of
complexes, fac-[99mΤc(CO)3(L)(im)], 2΄ and fac-[99mΤc(CO)3(L)(Η2Ο)], 1΄.
Addition of cycloexyl isocyanide to complex 1΄ in room temperature for 30 min
leads to complex fac-[99mΤc(CO)3(L)(isc)], 3΄. Addition of triphenylpsosphine
to complex 1΄ in 60 °C for 30 min results to complex fac-[99mΤc(CO)3(L)(PPh3)],
4΄, while addition of triphenylpsosphine in 95 °C for 30 min results to complex
trans-[99mΤc(CO)2(L)(PPh3)2], 5΄. All 99mΤc complexes were
characterized by RP-HPLC using the corresponding rhenium complexes as
references.
Their stability in presence of the challengers, histidine and cysteine, as well
as its
relation with time were studied too. All 99mΤc complexes were evaluated for
their “in
vitro” cellular uptake in B16F1 murine melanoma cells, were complex 5΄ had the
most promising results.
Keywords:
Radiopharmaceutical Re and Tc-99m, NO bidentate ligands, Tricarbonyl complexes, 2.3-pyrazinecarboxylic anhyride, Melanoma
