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Celen S, de Groot T, Balzarini J, Vunckx K, Terwinghe C, Vermaelen P, Van Berckelaer L, Vanbilloen H, Nuyts J, Mortelmans L, Verbruggen A, Bormans G: Synthesis and evaluation of a (99m) Tc-MAMA-propyl-thymidine complex as a potential probe for in vivo visualization of tumor cell proliferation with SPECT. Nucl Med Biol. 2007 Apr;34(3):283-91.
INTRODUCTION: Cytosolic thymidine kinase (TK1) catalyzes phosphorylation of thymidine to its monophosphate. TK1 activity is closely related with DNA synthesis, and thymidine analogs derivatized with bulky carboranylalkyl groups at the N-3 position were reported to be good substrates for TK1. Accordingly, we have synthesized (99m) Tc-MAMA-propyl-thymidine and evaluated it as a potential tumor tracer. METHODS: The bis (S-trityl)-protected MAMA-propyl-thymidine precursor (3-N-[S-trityl-2-mercaptoethyl]-N-[N'-(S-trityl-2-mercaptoethyl) amidoacety l]-aminopropyl-thymidine) was prepared in three steps, and its structure was confirmed with (1) H NMR and mass spectrometry. Deprotection of the thiols and labeling with (99m) Tc were done in a two-step, one-pot procedure, yielding (99m) Tc-MAMA-propyl-thymidine, which was analyzed with high-performance liquid chromatography, radio-LC-MS analysis (ESI+) and electrophoresis, and its log P was determined. The biodistribution in normal mice was evaluated, and its biodistribution in a radiation-induced fibrosarcoma (RIF) tumor mouse was compared with that of 3'-deoxy-3'-[(18) F] fluorothymidine [(18) F] FLT. RESULTS: (99m) Tc-MAMA-propyl-thymidine was obtained with a radiochemical yield of 70%. Electrophoresis indicated that the complex is uncharged, and its log P was 1.0. The molecular ion mass of the Tc complex was 589 Da, which is compatible with the hypothesized N (2) S (2)-oxotechnetium structure. Tissue distribution showed fast clearance from plasma primarily by the hepatobiliary pathway. Whole-body planar imaging after injection of (99m) Tc-MAMA-propyl-thymidine in an RIF tumor-bearing mouse showed high uptake in the liver and the intestines. No uptake was observed in the tumor, in contrast to the clear uptake observed for [(18) F] FLT visualized with muPET. CONCLUSIONS: Although it has been reported that TK1 accepts large substituents at the N-3 position of the thymine ring, the results of this study show that (99m) Tc-MAMA-propyl-thymidine cannot be used as a single photon emission computed tomography tumor tracer, probably because the (99m) Tc-MAMA ligand is too bulky to be tolerated by TK1. |
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