UNLABELLED: (99m)Tc-technetium ((99m)Tc) and (188)Re-rhenium ((188)Re) represent an interesting pair of radionuclides for diagnosis and therapy. The aim of this study was to synthesize and characterize in vitro/in vivo the first (188)Re-folate derivative [(188)Re(CO)(3)-picolylamine monoacetic acid 188/Re-OANA-folate (2)] for potential targeted radionuclide therapy of FR-positive tumors. The data were compared with those of the isostructural (99m)Tc-analog [(99m)Tc-PAMA folate (1)] reported previously. METHODS: In vitro stability of compound 2 was tested in phosphate-buffered saline and human plasma. Cell binding experiments were performed with FR-positive human KB cells. Biodistribution was assessed in female nude mice, bearing KB tumor xenografts. RESULTS: Cell binding experiments showed high and FR-specific uptake. In vivo, compound 2 accumulated specifically in the FR-positive tumors with maximal values 4 h post injection (p.i.) ['2: 1.87+/-0.04 percent injected dose per gram of weight tissue (% ID/g) vs. '1: 2.33+/-0.36% ID/g]. Unfavorably high retention of radioactivity was found in FR-positive kidneys (12.04+/-0.62% ID/g; 4 h p.i.). Tumor-to-blood ratio of radioactivity ('2: 14.5+/-1.32, 4 h p.i.) was lower than for compound '1 (58.0+/-12.2, 4 h p.i.), whereas tumor-to-kidney ratios were in the same range ('2: 0.15+/-0.01 vs. '1: 0.13+/-0.02, 4 h p.i.). Preadministration of the antifolate pemetrexed significantly improved the tumor-to-kidney ratio (2: 1.59+/-0.30, 4 h p.i.). CONCLUSIONS: The isostructural radiofolates 1 and '2 displayed almost identical pharmacokinetic profiles and accumulated both specifically in FR-positive tumors. However, only the coapplication of the antifolate pemetrexed improved the biodistribution of the radiotracers in such ways that a potential therapeutic application of compound '2 can be envisaged in the future.
UNLABELLED: (99m)Tc-technetium ((99m)Tc) and (188)Re-rhenium ((188)Re) represent an interesting pair of radionuclides for diagnosis and therapy. The aim of this study was to synthesize and characterize in vitro/in vivo the first (188)Re-folate derivative [(188)Re(CO)(3)-picolylamine monoacetic acid 188/Re-OANA-folate (2)] for potential targeted radionuclide therapy of FR-positive tumors. The data were compared with those of the isostructural (99m)Tc-analog [(99m)Tc-PAMA folate (1)] reported previously. METHODS: In vitro stability of compound 2 was tested in phosphate-buffered saline and human plasma. Cell binding experiments were performed with FR-positive human KB cells. Biodistribution was assessed in female nude mice, bearing KB tumor xenografts. RESULTS: Cell binding experiments showed high and FR-specific uptake. In vivo, compound 2 accumulated specifically in the FR-positive tumors with maximal values 4 h post injection (p.i.) ['2: 1.87+/-0.04 percent injected dose per gram of weight tissue (% ID/g) vs. '1: 2.33+/-0.36% ID/g]. Unfavorably high retention of radioactivity was found in FR-positive kidneys (12.04+/-0.62% ID/g; 4 h p.i.). Tumor-to-blood ratio of radioactivity ('2: 14.5+/-1.32, 4 h p.i.) was lower than for compound '1 (58.0+/-12.2, 4 h p.i.), whereas tumor-to-kidney ratios were in the same range ('2: 0.15+/-0.01 vs. '1: 0.13+/-0.02, 4 h p.i.). Preadministration of the antifolate pemetrexed significantly improved the tumor-to-kidney ratio (2: 1.59+/-0.30, 4 h p.i.). CONCLUSIONS: The isostructural radiofolates 1 and '2 displayed almost identical pharmacokinetic profiles and accumulated both specifically in FR-positive tumors. However, only the coapplication of the antifolate pemetrexed improved the biodistribution of the radiotracers in such ways that a potential therapeutic application of compound '2 can be envisaged in the future.