Isostructural folate conjugates radiolabeled with the matched pair 99mTc/188Re: a potential strategy for diagnosis and therapy of folate receptor-positive tumors

99mTc-technetium (99mTc) and 188Re-rhenium (188Re) 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 188Re-folate derivative [188Re(CO)3–picolylamine monoacetic acid 188Re-PAMA-folate (2)] for potential targeted radionuclide therapy of FR-positive tumors. The data were compared with those of the isostructural 99mTc-analog [99mTc–PAMA folate (1)] reported previously.MethodsIn 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.ResultsCell 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.).ConclusionsThe 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.