Supervisors info:
ΤΣΟΤΙΝΗΣ ΑΝΔΡΕΑΣ, Καθηγητής, Τομέα Φαρμακευτικής Χημείας, Φαρμακευτικη Αθηνων, ΕΚΠΑ
MΗΝΑΣ ΠΑΠAΔΟΠΟΥΛΟΣ, Ερευνητής Α΄, ΕΚΕΦΕ Δημόκριτος
ΙΩΑΝΝΗΣ ΠΙΡΜΕΤΤΗΣ, Ερευνητής Α΄, ΕΚΕΦΕ Δημόκριτος
Summary:
[2+1] mixed ligand complexes, fac-ML1L2(CO)3 (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, L1, and/or monodentate, L2, ligands. Recently, it was shown that when L1 is quinaldic acid (NO) and L2 is triphenylphosphine or isocyanide, M (NO)(P)(CO)3 or M (NO)(C)(CO)3, the carbonyl ligand found in trans position to the P or C donor atom is labilized and can be substituted by a second triphenylphosphine or isocyanide leading to [2+1+1] cis-trans-M(NO)(P)2(CO)2 or cis-trans-M(NO)(P)(C)(CO)2 dicarbonyl complexes. This expands even more the advantages of the [2+1] approach, offering more room for structural variability. Aiming at investigating further the [2+1] mixed ligand approach with a different bidentate ligand, herein is reported the synthesis and characterization of ten Re/99mTc complexes; two tricarbonyl trans-[Re/99mTc (SS)(isc)(CO)3] 1, 1’ and trans-[Re/99mTc(SS)(P)(CO)2] 2, 2’ and three dicarbonyl cis-trans-[Re/99mTc(SS)(isc)2(CO)2] 3, 3’, cis-trans-[Re/99mTc(SS)(P)2(CO)2] 4, 4’ and cis-trans-[Re/99mTc(SS)(P)(isc)(CO)2] 5, 5’, where (SS) is diethythiocarbamate, (P) is triphenylphosphine and (isc) is cyclohexylisocyanide.
Reaction of fac-[NEt4]2[ReBr3(CO)3] with equimolar amounts of (SS) and (isc) or (P) in refluxing methanol for 4 hours yielded the intermediate [2+1] tricarbonyl complexes fac-[Re(SS)(isc)(CO)3] ,1 and fac-[Re(SS)(P)(CO)3] ,2. To obtain complexes 3- 4, equimolar amounts of precursor fac-[NEt4]2[ReBr3(CO)3] and (SS) were reacted with excess of (isc) or (P) respectively in refluxing toluene for 7 hours. Complex 5 was obtained by reacting 1 with excess of (P) or by reacting 2 with excess of (isc) in refluxing toluene for 7 hours. The corresponding 99mTc complexes were synthesized in a similar procedure: Reaction of precursor [99mTc]fac-[Tc (H2O)3(CO)3]+ with (SS) and (isc) (10-3M) or (P) (10-3M) at 70 oC for 30 min resulted in complexes 1’ or 2’ respectively. Reaction of [99mTc]fac-[Tc (H2O)3(CO)3]+ with (SS) and (isc) or (P) (10-3 M) at 95 oC for 1 hour afforded complexes 3’ and 4’ respectively. Complex 5’ was obtained by reacting 1’ with (P) (10-3M) at 95 oC for 45 min.
Complexes 1 and 2 were resulted in high yield and complexes 3-5 were obtained in 55%, 85% and 30% yield, respectively. All complexes were fully characterized by elemental analysis and spectroscopic methods. The structure of 1-4 was confirmed by X-ray crystallography.
The yields of complexes 1’ and 2’ were >90%; on the other hand, the dicarbonyl complexes 3’-5’ yielded 40%, >95% and 28% respectively. All complexes were purified by HPLC and characterized by HPLC comparative studies, using as references the analogous well characterized Re complexes 1-5. All 99mTc complexes were stable at 37 °C in the presence of excess of histidine or cysteine at pH 7.4 for at least 6 hours. LogP values for 1’-5’ were 3.39, 2.96, 2.60, 1.06 and 2.04, respectively. All complexes were evaluated biologically in vivo, after intravenous injection of the complexes into Swiss Albino mice at 2 minutes, 2 hours, and 4 hours intervals. Finally, all the complexes proved to be stable also in vivo and the biological results differed according to the ligand used.
We successfully synthesized and characterized three novel dicarbonyl cis-trans-M(SS)(isc)2(CO)2, cis-trans-M(SS)(P)2(CO)2 and cis-trans-M(SS)(P)(isc)(CO)2 (M=99mTc/Re), by gradual replacement of a carbonyl ligand by isocyanide and/or triphenylphosphine. These model compounds may prove useful for the development of multimodal complexes for nuclear medicine applications.
Keywords:
Radiopharmacy, Inorganic Chemistry, Technetium, Rhenium, Building Blocks
