A New ¹⁸F-Labeled Folic Acid Derivative with Improved Properties for the PET Imaging of Folate Receptor–Positive Tumors

Abstract

The folate receptor is a proven target for folate-based diagnosis and treatment of cancer. Several folic acid conjugates have been developed as radiopharmaceuticals, but a suitable 18 Flabeled folic acid derivative for routine clinical use is still lacking. The purpose of this study was to investigate the potential of 29-18 F-fluorofolic acid as a PET agent for folate receptor-positive tumors. Methods: The binding affinity of the cold reference compound 29-fluorofolic acid was determined by in vitro displacement assays using human folate receptor-positive KB cells and 3 H-folic acid. 18 F labeling of 29-fluorofolic acid was accomplished via a direct nucleophilic aromatic substitution of N 2 -(N,N-dimethylamino-methylene)-29-nitrofolic acid di-tertbutylester followed by acidic cleavage of the amino and carboxylic protecting groups. The new radiofolate was evaluated in nude mice bearing KB tumor xenografts under control and blocking conditions. Animals were either scanned from 75 to 105 min after injection of the radiotracer or sacrificed 75 min after injection for ex vivo biodistribution studies. Results: 29-fluorofolic acid showed a high binding affinity (inhibition constant, 1.8 6 0.1 nM) for the folate receptor. Direct aromatic 18 F labeling of 29-fluorofolic acid was achieved within 80 min via a convenient 2-step procedure in satisfactory radiochemical yields. The new radiotracer exhibited excellent pharmacokinetics with fast renal clearance and only moderate hepatobiliary elimination. Uptake of 29-18 F-fluorofolic acid in folate receptorpositive KB tumors was high and specific, allowing a clearcut visualization by PET. Conclusion: 29-18 F-fluorofolic acid, obtained via an integrated approach, is a promising PET agent for folate receptor-positive tumors and outperforms previously reported 18 F-labeled folates.

Synthesis and Preclinical Evaluation of Folate-NOTA-Al18F for PET Imaging of Folate-Receptor-Positive Tumors

“…33–56 Our motivation for seeking yet another folate-targeted PET agent was prompted by the need to create an imaging agent that could meet the economic requirements for translation of a PET agent into the clinic. 18 F was selected ahead of 68 Ga not only because of the higher resolution images that it yields, 28, 57–59 but also because of the extensive production and distribution networks that already exists for 18 F. 58 Folate-NOTA-Al 18 F was preferred over earlier folate- 18 F conjugates for reasons that differ for each previous conjugate, including its higher specific activity, 39, 45, 47, 55 comparable or in some cases better radiochemical yield, 39, 40, 47, 49 and faster or simpler synthesis. 39, 40, 47, 49, 51 As a consequence, we propose that folate-NOTA-Al 18 F meets most of the requirements for eventual translation into human clinical trials.…”

Folate receptor: a potential target in ovarian cancer

“…Fischer et al used the efficacy of CuAAC for 18 F-radiolabeling in combination with the inevitable polarity of [ 18 F]FDG to enhance pharmacodynamics and significantly enhanced tumor-to-background ratio [52]. Another approach is 18 F-fluorination, which led to the development of 2′-[ 18 F]fluorofolic acid with promising results in vivo, as a clear-cut visualization of FR-positive KB tumors, and healthy tissues have been shown [53,54]. Recently, several new 18 F-folate was developed, being available in very high radiochemical yields via a fast and convenient two-step radiosynthesis and showed good in vivo behavior waiting for testing in clinical trials [49,55].…”

Development of a New Folate-Derived Ga-68-Based PET Imaging Agent

“…As a matter of fact, numerous of folate-conjugated PET agents have already been proven to visualize FR-positive tumors in vivo [3, 28–31, 33–38]. In the past, different approaches were utilized for the synthesis of folate-based PET radiotracers.…”

“…In the past, different approaches were utilized for the synthesis of folate-based PET radiotracers. To our knowledge, current preclinical PET imaging tracers are based on either F-18 [14, 28–30, 33, 38] or Ga-68 [3, 31, 34–37] as a radionuclide for in vivo imaging. All imaging tracers were able to successfully delineate folate receptor-positive tumors in animal models.…”