Summary:
The nuclear isomer technetium-99m (99mTc) is the most important radionuclide with wide diagnostic applications over 80% in Nuclear Medicine. In addition, 99mTc shares a very similar chemistry with isotopes 186 and 188 of its heavier homolog rhenium (186/188Re), high energy β-particle-emmiters. It represents one of the first and ideal pairs for development of “theranostics”, the designed combination of therapeutic and diagnostic procedures. The study of coordination chemistry of 99mTc/Re can be applied for development of new more efficient diagnostic and/or therapeutic radiopharmaceuticals. [2+1] mixed-ligand fac-[M(I)(CO)3]+ complexes (M=99mTc/Re), are characterized by kinetic stability and offer a unique combinatorial advantage since they allow the flexibility to tailor their physicochemical properties by adjusting the bidentate and/or monodentate ligands. In an effort to expand even more the advantages of the [2+1] approach, we report in this dissertation a series of novel [2+1] mixed-ligand complexes of the general type fac-[99mTc/Re(CO)3(ΑΒ)(P)], where (ΑΒ) is four different bidentate ligands, quinaldic acid (quinH), picolinic acid (picH), sodium dimethyldithiocarbamate (NaMe2SS) and sodium diethyldithiocarbamate (NaEt2SS) combined with two water-soluble phosphine (P) as monodentate ligands, 1,3,5-triaza-7-phosphaadamantane (PTA) and its recently synthesized higher homologue 1,4,7-triaza-9-phosphatricyclo[5.3.214,9]tridecane (CAP).
At 185/187Re level, (N,O) complexes, fac-[Re(CO)3(quin)(PTA)] (1α), fac-[Re(CO)3(quin)( CAP)] (1β) and fac-[Re(CO)3(pic)(PTA)] (2α), fac-[Re(CO)3(pic)(CAP)] (2β), were synthesized via the corresponding aqua Re complexes fac-[Re(CO)3(quin)(H2O)] (1) and fac-[Re(CO)3(pic)(H2O)] (2). On the other hand, (S,S) complexes, fac-[Re(CO)3(Me2SS)(PTA)] (3α), fac-[Re(CO)3(Me2SS)( CAP)] (3β) and fac-[Re(CO)3(Et2SS)(PTA)] (4α), fac-[Re(CO)3(Et2SS)(CAP)] (4β), were formed by employing one-pot methodology, by reacting equimolar amounts of the corresponding (S,S), phosphine ligand and rhenium precursor. The [2+1] complexes were prepared in generally high yields and purity. All rhenium complexes were fully characterized by elemental analysis and spectroscopic methods (IR, 1Η, 13C, 31P-NMR). Additionally, the structure of 1β, 2β, 4α, 4β was confirmed by X-ray crystallography.
At the 99mTc tracer level, essentially the same steps are followed, starting from the fac-[99mTc(CO)3(H2O)3]+ precursor. Thus, the corresponding 99mTc complexes (1α΄, 1β΄, 2α΄, 2β΄, 3α΄, 3β΄, 4α΄, 4β΄) were synthesized. These complexes were produced in high radiochemical purity, characterized by comparative Reverse Phase High Performance Liquid Chromatography (RP-HPLC), and showed high resistance to transchelation by cysteine or histidine. The lipophilicity of the complexes ranged from -0.53 to 2.89. Biodistribution in experimental healthy mice showed that the brain uptake of complexes 3α΄, 3β΄, 4α΄, 4β΄ at 2 min after i.v. is noteworthy (8.08, 10.73, 4.93, 1.80 % ID/g, respectively).
In conclusion, novel [2+1] mixed-ligand complexes fac-[99mTc/Re(CO)3(ΑΒ)(P)] (AB = quin , pic, Me2SS or Et2SS) were synthesized successfully conjugated with a water-soluble monodentate ligand (P = PTA or CAP). These could contribute to the development of new multimodal radiopharmaceuticals for Nuclear Medicine applications.
