The
folate receptor (FR) is highly expressed on most epithelial
cancer cells, while normal cells show only restricted expression of FR. As a result, the FR is an ideal target for receptor-based molecular imaging and
therapy of
cancer and has become a promising target in oncology. To date, several
folate-based chemotherapeutics and imaging probes such as
radiopharmaceuticals for single photon emission computed tomography (SPECT) have been developed. However, an (18)F-labeled
folic acid derivative suitable for positron emission tomography (PET) imaging that can be routinely applied is still lacking. In this study, a new fluorinated and radiofluorinated
folic acid derivative, (18/19)F-click
folate, was synthesized using click chemistry. In a convenient and very efficient two-step radiosynthesis, the isolated (18)F-click
folate was obtained in good radiochemical yields of 25-35% with a specific activity of 160+/-70 GBq/micromol after <or=90 min synthesis time. The new compound was pharmacologically evaluated in vitro and in vivo. The affinity of the non-radioactive (19)F-click
folate to the FR was determined in displacement studies with FR expressing KB
tumor cells using (3)H-folic
acid. In these in vitro binding studies, a nanomolar affinity with a K(i) of 9.76+/-3.13 nM was found for (19)F-click
folate. The (18)F-labeled click
folate derivative was then applied for in vivo PET studies and ex vivo biodistribution experiments using nude mice bearing KB
tumor xenografts. The post mortem dissection experiments showed a high specific uptake of (18)F-click
folate derivative in FR-expressing tissues. Uptake in KB
tumor xenografts and kidneys (FR-positive tissue) amounted to 3.13%ID/g (94% specific blockade) and 16.53%ID/g (75% specific blockade), respectively. PET imaging using (18)F-click
folate permitted a visualization of KB
tumors, and blockade studies confirmed the specific accumulation of the radiotracer in vivo. However, strong hepatobiliary excretion of the new tracer led to elevated accumulation of radioactivity in the abdominal region. In conclusion, the click chemistry approach is convenient to accomplish and provided high radiochemical yields of (18)F-click
folate. The new tracer showed good in vitro but limited in vivo properties. Ultimately, the (18)F-click
folate emphasizes the potential of (18)F-labeled folates for receptor-based
tumor PET imaging.