Supervisors info:
Τσοτίνης Ανδρέας, Καθηγητής Τομέας Φαρμακευτικής Χημείας του τμήματος Φαρμακευτικής του Εθνικού και Καποδιστριακού Πανεπιστημίου Αθηνών
Παπαδόπουλος Μηνάς, Α' Ερευνητης του Τμήματος Ραδιοφαρμακευτικής του Ινστιτούτου Ραδιοϊσοτόπων και Ραδιοδιαγνωστικών Προϊόντων του ΕΚΕΦΕ Δημόκριτος
Summary:
In the current work, we present the synthesis and characterization of novel mixed-ligand fac-[M(CO)3(PO)N] complexes, whereby PO is the monoanionic bidentate (2-hydroxyphenyl)diphenylophosphine and N is a neutral monodentate ligand, a substituted pyridine (NN-diethylnicotinamide, isonicotinic acid, nicotinic acid, pyridine, N-pyridin-4yl-acetamide, 4-methoxypyridine, 4-aminopyridine,4-dimethyloaminopyridine).
Initially, POH reacted in equimolar amounts with the [Et4N]2[Re(CO)3Br3] precursor to afford fac-[Re(CO)3(PO)(H2O)], complex II (yield 75%). Complex II readily reacted with N under formation of fac-[Re(CO)3(PO)(4pyCONHNH2)], 1, fac-[Re(CO)3(PO)(3pyCONEt2)], 2, fac-[Re(CO)3(PO)(4pyCOOH)], 3, fac-[Re(CO)3(PO)(3pyCOOH)], 4, fac-[Re(CO)3(PO)(py)], 5, fac-[Re(CO)3(PO)(4pyNHCOCH3)], 6, fac-[Re(CO)3(PO)(4pyOMe)], 7, fac-[Re(CO)3(PO)(4pyNH2)], 8, fac-[Re(CO)3(PO)(4pyNMe2)], 9. All complexes were obtained in high yield (>87%). The Re-complexes 1-9 were fully characterized by NMR, IR. Single crystals of 3, 4, 7 and 8 complexes where obtained and analyzed by X-ray diffraction analysis.
The impact of the dissociation constant (pka) of the substituted pyridine was evident in the Re-complexes. 8', has the shortest Re-N bond length (2.227 Å), while 3' has the longest Re-N bond length (2.236 Å).
Complexes 1΄- 9΄ formed at tracer level in high radiochemical yield (> 95%) by a one-pot reaction of POH and Ν with the fac-[99mTc(CO)3(H2O)3]+ precursor at 70 °C for 30 min. The structure of 99mTc-complexes could be assigned by chromatographic comparison with their authentic Re-congeners adopting twin radio- (99mTc) and photometric (Re) detection modes.
In technetium level the results showed a linear correlation between the pKa and the resulting radiochemical yield. The series which is formed is: 1' > 2' > 3' > 4' > 5' > 6' > 7' > 8' > 9'. Also, the 1'-9' were subjected to amino acid challenge studies with cysteine and histidine to determine their stability at 37 oC for 1,3 and 6 h.
. The impact of N-nitrogen (1' > 2' > 3' > 4' > 5' > 6' > 7' > 8' > 9') was evident, with the complex 9΄ exhibiting the highest stability (84% under cysteine challenge and 74% under histidine challenge). Hence, fac-[99mTc(CO)3(PO)(4pyNMe2)] is the analog of choice for further radiopharmaceutical design.
