The synthesis and evaluation of N1-(4-(2-[18F]-fluoroethyl)phenyl)-N8-hydroxyoctanediamide ([18F]-FESAHA), A PET radiotracer designed for the delineation of histone deacetylase expression in cancer

Abstract Introduction Given the significant utility of suberoylanilide hydroxamic acid (SAHA) in chemotherapeutic protocols, a PET tracer that mimics the histone deacetylase (HDAC) inhibition of SAHA could be a valuable tool in the diagnosis, treatment planning and treatment monitoring of cancer. Here, we describe the synthesis, characterization and evaluation of N 1 -(4-(2-[ 18 F]-fluoroethyl)phenyl)- N 8 -hydroxyoctanediamide ([ 18 F]-FESAHA), a PET tracer designed for the delineation of HDAC expression in cancer. Methods FESAHA was synthesized and biologically characterized in vivo and in vitro . [ 18 F]-FESAHA was then synthesized in high radiochemical purity, and the log P and serum stability of the radiotracer were determined. In vitro cellular uptake experiments and acute biodistribution and small-animal PET studies were performed with [ 18 F]-FESAHA in mice bearing LNCaP xenografts. Results [ 18 F]-FESAHA was synthesized in high radiochemical purity via an innovative one-pot procedure. Enzymatic inhibition assays illustrated that FESAHA is a potent HDAC inhibitor, with IC 50 values from 3 nM to 1.7 μM against the 11 HDAC subtypes. Cell proliferation experiments revealed that the cytostatic properties of FESAHA very closely resemble those of SAHA in both LNCaP cells and PC-3 cells. Acute biodistribution and PET imaging experiments revealed tumor uptake of [ 18 F]-FESAHA and substantially higher values in the small intestine, kidneys, liver and bone. Conclusion The significant non-tumor background uptake of [ 18 F]-FESAHA presents a substantial obstacle to the use of the radiotracer as an HDAC expression imaging agent. The study at hand, however, does present a number of lessons critical to both the synthesis of hydroxamic acid containing PET radiotracers and imaging agents aimed at delineating HDAC expression.