Novel synthesis and preclinical evaluation of folic acid derivatives labeled with (18)F-[FDG] for PET imaging of folate receptor-positive tumors

There is a need to develop more potent radiofluorinated folic acid conjugates for a better visualization of folate receptors that overexpress on many human cancers. Due to the clinical importance of [¹⁸F]-fluoro-2-deoxy-d-glucose ([¹⁸F]-FDG) and its availability in almost every positron-emission tomography center, new radiofluorinated [¹⁸F]-FDG-folate and methotrexate conjugates ([¹⁸F]-5 and [¹⁸F]-8) were synthesized using [¹⁸F]-FDG as a prosthetic group. In a convenient and simple one-step radiosynthesis, [¹⁸F]-5 and [¹⁸F]-8 conjugates were prepared in high radiochemical yields (> 80%) with total synthesis time of almost 20 min, and radiochemical purities were found to be greater than 98% without high-performance liquid chromatography purification, which make these approaches amenable for automation. In vitro tests on KB cell line showed that a significant amount of the radioconjugates were associated with the cell fractions. In vivo characterization in normal Balb/c mice revealed rapid blood clearance of these radioconjugates with excretion predominantly by the urinary and hepatobiliary systems for [¹⁸F]-5 and [¹⁸F]-8 conjugates, respectively. Biodistribution studies in nude mice-bearing human KB cell line xenografts demonstrated significant tumor uptake and favorable kinetics profile for [¹⁸F]-5 over the other conjugate. The uptake in the tumors was blocked by the excess coinjection of cold folic acid, suggesting the receptor-mediated process. These results demonstrate that [¹⁸F]-5 may be useful as a molecular probe for detecting and staging of folate receptor-positive cancers, such as ovarian cancer and their metastasis, as well as monitoring tumor response to the treatment.