By analogy to the recently described single amino acid chelate (SAAC) technology for complexation of the {M(CO)3}+ core (M = Tc, Re), a series of tridentate ligands containing thiolate and thioether groups, as well as amino and pyridyl nitrogen donors, have been prepared: (NC5H4CH2)2NCH2CH2SEt (L1); (NC5H4CH2)2NCH2CH2SH (L2); NC5H4CH2N(CH2CH2SH)2 (L3); (NC5H4CH2)N(CH2CH2SH)(CH2CO2R) [R = H (L4); R = -C2H5 (L5). The {Re(CO)3}+ core complexes of L1-L5 were prepared by the reaction of [Re(CO)3(H2O)3]Br or [NEt4]2[Re(CO)3Br3] with the appropriate ligand in methanol and characterized by infrared spectroscopy, 1H and 13C NMR spectroscopy, mass spectrometry, and in the case of [Re(CO)3(L2)] (Re-2) and [Re(CO)3(L1)Re(CO)3Br2] (Re-1a) by X-ray crystallography. The structure of Re-2 consists of discrete neutral monomers with a fac-Re(CO)3 coordination unit and the remaining coordination sites occupied by the amine, pyridyl, and thiolate donors of L2, leaving a pendant pyridyl arm. In contrast, the structure of Re-1a consists of discrete binuclear units, constructed from a {Re(CO)3(L1)}+ subunit linked to a {Re(CO)3Br2}- group through the sulfur donor of the pendant thioether arm. The series of complexes establishes that thiolate donors are effective ligands for the {M(CO)3}+ core and that a qualitative ordering of the coordination preferences of the core may be proposed: pyridyl nitrogen approximately thiolate > carboxylate > thioether sulfur > thiophene sulfur. The ligands L1 and L2 react cleanly with [99mTc(CO)3(H2O)3]+ in H2O/DMSO to give [99mTc(CO)3(L1)]+ (99m)Tc-1) and [99mTc(CO)3(L2)] (99mTc-2), respectively, in ca. 90% yield after HPLC purification. The Tc analogues 99mTc-1 and 99mTc-2 were subjected to ligand challenges by incubating each in the presence of 1000-fold excesses of both cysteine and histidine. The radiochromatograms showed greater than 95% recovery of the complexes.
The reaction of biotinamine with two equivalents of 2-quinoline aldehyde in the presence of Na(OAc)3BH in dichloroethane provides N,N-bis(methylquinoline)biotinamine (L1), a molecule displaying a tridentate donor terminus which has proven effective in coordinating to the {M(CO)3}+ core (M = Tc, Re). Reaction of L1 with (NEt4)2[Re(CO)3Br3] yields [Re(CO)3(L1)]Br, a compound with an absorbance at 350 nm and luminescence emission maxima at 425 and 580 nm. The luminescence lifetime of 11.4 mus, which is associated with the 580 nm emission, is sufficiently prolonged to enable time-gating techniques to be used during in vitro imaging studies and to overcome interference from endogenous fluorescence. Exposure of avidin beads to {Re(CO)3(L1)]Br resulted in binding, which was qualitatively imaged using fluorescence microscopy. The 99mTc analogue [99mTc(CO)3(L1)]+1 was prepared by reacting L1 with [99mTc(CO)3(H2O)3]+1 and purified by HPLC. The 99mTc complex is chemically robust and resistant to cysteine and histidine challenges. This study demonstrates that complementary fluorescent and radioactive biotin-derived probes may be readily prepared to allow direct correlation of in vitro and in vivo molecular imaging studies.
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