Summary:
In the present work, the synthesis and characterization of new Re and 99mTc
mixed ligand complexes at oxidation state (I) is described. For that purpose,
the fac-[M(CO)3]+ synthon (Μ = Re or 99mTc) is used and the [2 + 1] approach is
applied. In order to prepare the new complexes, two bidentate ligands are used,
namely curcumin (curc) and quinaldic acid (quin), with atoms donors OO or NO
respectively. In the case of curcumin, the first step comprises of its
coordination to the metal core fac-[Re(CO)3]+ and the formation of the complex
fac-[Re(curc)(H2O)(CO)3], 1. Then, the replacement of the water molecule by
various monodentate ligands namely imidazole (im), triphenylphosphine (PPh3)
and cyclohexylisocyanide (cisc), leads each time to the formation of a single
product, namely fac-[Re(curc)(im)(CO)3], 2, fac-[Re(curc)(PPh3)(CO)3], 3,
trans-cis-[Re(curc)(PPh3)2(CO)2], 4 and fac-[Re(curc)(cisc)(CO)3], 5. All the
Re complexes were fully characterized by elemental analysis, IR and 1H NMR
spectroscopy. The structure of complex 5 was established by X-rays
crystallography.
At 99mTc level, addition of curcumin to the fac-[99mTc(H2O)3(CO)3]+ precursor
leads to the formation of fac-[99mTc(curc)(Η2Ο)(CO)3], 1΄, in high
radiochemical purity. Complexes 2΄ – 5΄ are also prepared by adding the
appropriate monodentate ligand to the labelling solution of 1΄. All the 99mTc
complexes are characterized by comparative HPLC using the analogous
well-characterized Re complexes as reference. Stability of the 99mTc complexes
(Cys/His challenge and plasma stability) and lipophilicity were studied, as
well as biodistribution in experimental mice. Biodistribution data showed that
the brain uptake of complexes 1΄, 3΄ - 5΄ at 2 min p.i is 0.46 – 1.07 % ID/g.
In the second part, quinaldic acid as a NO monoanionic bidentate ligand is
used. Initially, the Re complexes are prepared by coordination of quinaldic
acid to the metal core fac-[Re(CO)3]+ and the formation of complex
fac-[Re(quin)(H2O)(CO)3], 6. Then, the water molecule is replaced by various
monodentate ligands namely imidazole (im), triphenylphosphine (PPh3),
trimethylphosphite (POM), tris(hydroxymethyl)phosphine (THP), triphenylarsine
(AsPh3), cyclohexylisocyanide (cisc) and
N-[4-(benzothiazol-2-yl-phenyl)-3-isocyano-propionamide (bisc), which was
synthesised for this purpose. Consequently, the complexes
fac-[Re(quin)(im)(CO)3], 7, fac-[Re(quin)(PPh3)(CO)3], 8,
trans-cis-[Re(quin)(PPh3)2(CO)2], 9, fac-[Re(quin)(POM)(CO)3], 10,
fac-[Re(quin)(THP)(CO)3], 11, fac-[Re(quin)(AsPh3)(CO)3], 12,
fac-[Re(quin)(cisc)(CO)3], 13 and fac-[Re(quin)(bisc)(CO)3], 14, are prepared.
It is worth noticed that bisc bears the 2-(4-aminophenyl)benzothiazole moiety,
which binds with high affinity to amyloid plaques of Alzheimer’s disease. All
the Re complexes were fully characterized by elemental analysis, IR and 1H NMR
spectroscopy. The structure of complexes 6 - 8 and 10 - 12 was established by
X-rays crystallography. At 99mTc level, addition of quinaldic acid to the
fac-[99mTc(H2O)3(CO)3]+ precursor leads to the formation of
fac-[99mTc(quin)(Η2Ο)(CO)3], 6΄, with high radiochemical purity. Complexes 7΄ –
13΄ are also formed by adding the appropriate monodentate ligand to 6΄ and are
characterized by comparative HPLC using the analogous well-characterized Re
complexes as reference. Experimental data showed that the complex 13΄ has
excellent characteristics in order to further act as a “building block” for the
development of novel target-specific radiopharmaceuticals. That is why the
ligand bisc and its corresponding complex fac-[99mTc(quin)(bisc)(CO)3], 14΄
were synthesized. The stable and lipophilic complex 14΄ showed brain uptake of
0.42 % ID/g, 2 min p.i. in experimental mice.
