Isostructural folate conjugates radiolabeled with the matched pair 99mTc/188Re: a potential strategy for diagnosis and therapy of folate receptor-positive tumors.
(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.
Müller
Cristina
C
Center for Radiopharmaceutical Science ETH-PSI-USZ, Paul Scherrer Institute, 5232 Villigen-PSI, Switzerland.
Schubiger
P August
PA
Schibli
Roger
R
D000818:Animals; D000970:Antineoplastic Agents / Q000493:pharmacokinetics / Q000627:therapeutic use; D002021:Buffers; D002352:Carrier Proteins / Q000378:metabolism*; D005260:Female; D058973:Folate Receptors, GPI-Anchored; D005492:Folic Acid / Q000737:chemistry*; D005493:Folic Acid Antagonists / Q000493:pharmacokinetics / Q000627:therapeutic use; D005971:Glutamates / Q000493:pharmacokinetics / Q000627:therapeutic use; D006147:Guanine / Q000031:analogs & derivatives / Q000493:pharmacokinetics / Q000627:therapeutic use; D006801:Humans; D007553:Isotope Labeling; D007624:KB Cells; D007668:Kidney / Q000378:metabolism; D051379:Mice; D008819:Mice, Nude; D009368:Neoplasm Transplantation; D009369:Neoplasms / Q000188:drug therapy* / Q000378:metabolism*; D000068437:Pemetrexed; D010710:Phosphates / Q000737:chemistry; D011868:Radioisotopes; D019275:Radiopharmaceuticals / Q000138:chemical synthesis / Q000737:chemistry* / Q000493:pharmacokinetics; D011956:Receptors, Cell Surface / Q000378:metabolism*; D012211:Rhenium / Q000737:chemistry*; D013667:Technetium / Q000737:chemistry*; D014018:Tissue Distribution
D000970:Antineoplastic Agents; D002021:Buffers; D002352:Carrier Proteins; D058973:Folate Receptors, GPI-Anchored; D005493:Folic Acid Antagonists; D005971:Glutamates; D010710:Phosphates; D011868:Radioisotopes; D019275:Radiopharmaceuticals; D011956:Receptors, Cell Surface; D000068437:Pemetrexed; D006147:Guanine; D012211:Rhenium; D013667:Technetium; D005492:Folic Acid