Summary:
The synthesis, characterization and evaluation of neutral mixed ligand fac-
[Re/99mTc(CO)3L2L1] complexes, containing a monoanionic bidentate L2 and a
monodentate
ligand L1, are particularly interesting for the development of new
hexacoordinated complexes
that display stability against trans-chelation reactions. Coupling of a vector
to one ligand and
tuning of pharmacokinetics with the other provides excellent design versatility.
In this work, we have synthesized neutral mixed-ligand of the general form fac-
[Re/99mTc(CO)3(PO)L1] complexes, containing the (2-hydroxyphenyl)
diphenylphosphine
(POH) ligand. For such purposes, the fac-[Re(CO)3(PO)(H2O)], 1 has been
synthesized after
reaction of POH with [Et4N]2[ReBr3(CO)3]. However, excess of POH results in the
formation
of the mixed ligand fac-[Re(CO)3(PO)(POH)] complex, 2, where POH acts as both a
bidentate
and a monodentate ligand. Complex 1 is practically used as a precursor owing to
the presence
of the labile water molecule which can be readily replaced by a variety of
monodentate ligands,
such as pyridine (py), imidazole (im), cyclohexyl isocyanide (cisc) and
tert-butyl isocyanide
(tbi). The neutral complexes, fac-[Re(CO)3(PO)(pyr)], 3, fac-[Re(CO)3(PO)(im)],
4, fac-
[Re(CO)3(PO)(cisc)], 5 and fac-[Re(CO)3(PO)(tbi)], 6, were readily obtained in
high yield.
All complexes have been fully characterized by elemental analysis, IR and NMR
spectroscopies. Their solid-state structure has been elucidated by X-ray
crystallography.
At 99mTc level, complexes 1΄ – 6΄ are formed in high yield by adding POH and the
appropriate monodentate ligand and characterized by comparative HPLC studies
after coinjection
with the authentic Re-complexes.
During histidine and cysteine challenge experiments at 36oC for 6 hours all
complexes
remained stable. Examination of the logP data suggests high lipophilicity for
all complexes.
The values of logP are in the range of about 1.2 to 1.66. Biodistribution
studies of the stable
and lipophilic complex 2΄ in normal Swiss Albino mice at 1 hour, 4 and 24 hours
showed that
the complex is stable in vivo and the activity was excreted mainly through the
hepatobiliary
system. Finally, scintigraphic imaging using γ-camera confirms the results of
biodistribution.
Keywords:
Technetium99m, Rhenium, Complexes, Radiopharmaceutical chemistry, Labeling