Summary:
Technetium-99m and rhenium-188 radiopharmaceuticals play an important role in
Nuclear Medicine. The most useful diagnostic radionuclide in Nuclear Medicine
is technetium-99m, which is used in SPECT imaging. The fac-[Tc/Re(CO)3]+
moiety is used for the synthesis of novel radiopharmaceutical compounds because
of its small, spherical size and kinetic stability. Due to these properties the
development of new rhenium and technetium tricarbonyl complexes is currently an
active research area. The strategy for the development of fac-[Tc(CO)3]+-type
radiopharmaceuticals is primarily based on the use of tridentate ligands that
lead to in vivo stable complexes. Recently, the use of the combination of a
bidentate and a monodentate ligands (‘2+1’ mixed ligand system) has also been
proposed, which also leads to the formation of full-shell in vivo stable
complexes. Additionally the fac-[Tc(CO)3(“2+1”)]+ complexes offer the
advantage of greater flexibility in the design.This thesis is focused on the
development of novel Re/99mTc tricarbonyl complexes of the ‘2+1’ type, with
aromatic aminothiol (NS) bidentate ligands as model complexes for the
development of radiopharmaceuticals. In particular, the design, synthesis and
characterization of six new carbonyl rhenium (I) complexes and five new
carbonyl technetium (I) complexes was accomplished. The complexes of the
general type of dimerics [Μ(CO)3(NS)]2, mixed ‘2+1’ [Μ(CO)3(NS)(L)] and trans
-bisphosphine [Μ(CO)2(NS)(P2)] were studied, where M is rhenium or
technetium-99m, NS are 8-mercaptoquinoline (Sqn) or 2-mercaptopyridine (Spy), L
triphenylphosphine or benzylisocyanide (CNBn) and P triphenylphosphine.The
dimeric complexes [Re(CO)3(NS)]2 where NS are 8-mercaptoquinoline (Re1) and
2-mercaptopyridine (Re2) respectively, were synthesized by reaction of the
Re(I) precursors fac-(NEt4)2[ReBr3(CO)3] or [ReBr(CO)5] with the bidentate
ligands. The syntheses of the ‘2+1’ complexes of the formula [Re(CO)3(NS)(P)],
where NS are Sqn for Re3 and Spy for Re4, were performed by reaction of Re1 and
Re2 with PPh3, or alternatively in the case of Re3 by reaction of fac-[(NEt4)2
[ReBr3(CO)3] with 8-mercaptoquinoline and triphenylphosphine in a single step.
The syntheses of the respective trans-bisphosphine products [Re(CO)2(NS)P2]
were accomplished by reaction of mer, trans-[Re(CO)3(PPh3)2CI] with
8-mercaptoquinoline (Re5) and 2-mercaptopyridine (Re6). The reaction for the
synthesis of Re4 led to the formation of only one product as shown by TLC and
HPLC analysis. However, both reactions described above for the synthesis of Re3
, led to the formation of Re5 as minor product (<40%), while extended heating
with excess of triphenylphosphine yielded Re5 as the major product (>80%). The
mixed complex [Re(CO)3(Sqn)(CNBn)] (Re7) was synthesized by reaction of
benzylisonitrile with the Re1. All complexes were characterized by ΝΜR, FT-IR
and elemental analysis. Moreover, the structure of complexes Re3-Re6 was
elucidated by X-ray crystallography, which was shown to be distorted
octahedral. Furthermore, the complexes Re3, Re5, Re7 were shown to be
fluorescent and their emission spectra were recorded.At the tracer level (99m
Tc), the dimeric complex [99mTc(CO)3(Sqn)]2 99mTc1 was quantitatively
synthesized from the precursor fac-[99mTc(H2O)3(CO)3]+ by heating at 80 οC for
30 minutes with Sqn (10-3M). The analogous dimeric complex with Spy [99mTc(CO)3
(Spy)]2 99mTc2 however, could only be formed at very low yield (<10%) even at
>10-3M Spy concentration. The “2+1” mixed ligand complex [99mTc(CO)3(Sqn)P] 99m
Tc3 was synthesized from 99mTc1 by addition of triphenylphosphine at 35 οC with
60% yield, whereas by heating at higher temperature the bisphosphine complex
[99mTc(CO)2(Sqn)P2] 99mTc5 was quantitatively formed. The latter is also
synthesized in >95% yield from fac-[99mTc(H2O)3(CO)3]+ by addition of Sqn and
PPh3 (10-3M each) at 80 οC for 30 min. The “2+1” mixed ligand complex [99m
Tc(CO)3(Spy)P] 99mTc4 was synthesized quantitatively from fac-[99mTc(H2O)3(CO)3
]+ by addition of Spy and PPh3 (at 10-3M each) at 80 οC for 30 min. Complex
[99mTc(CO)3(Sqn)(CNBn)] 99mTc7 was synthesized from 99mTc1 by addition of
benzylisocyanide at 80 οC for 30 minutes. The identification of all 99mTc
labeled complexes was done by comparative RP-HPLC analysis with the analogous
fully characterized rhenium complexes by application of parallel photometric
and radiometric detection. In vitro studies showed that 99mTc4 is stable at
least for 24 hours in 1mM L-Histidine and 1mM L-Cysteine.These results show
that the “2+1” complex 99mTc4 can be prepared in high yield, is in-vitro stable
and therefore can be used as a model complex for the development of novel 99mTc
radiopharmaceuticals.
