18F-Fluorosulfate for PET Imaging of the Sodium-Iodide Symporter: Synthesis and Biologic Evaluation In Vitro and In Vivo

Anion transport by the human sodium-iodide symporter (hNIS) is an established target for molecular imaging and radionuclide therapy. Current radiotracers for PET of hNIS expression are limited to 1241 and F-18-BF4-. We sought new F-18-labeled hNIS substrates offering higher specific activity, higher affinity, and simpler radiochemical synthesis than F-18-BF4-. Methods: The ability of a range of anions, some containing fluorine, to block (99)mTcO(4)(-) uptake in hNIS-expressing cells was measured. SO3F- emerged as a promising candidate. F-18-SO3F- was synthesized by reaction of F-18- with SO3-pyridine complex in MeCN and purified using alumina and quaternary methyl ammonium solid-phase extraction cartridges. Chemical and radiochemical purity and serum stability were determined by radiochromatography. Radio tracer uptake and efflux in hNIS-transduced HCT116-C19 cells and the hNIS-negative parent cell line were evaluated in vitro in the presence and absence of a known competitive inhibitor (NaClO4). PET/CT imaging and ex vivo biodistribution measurement were conducted on BALB/c mice, with and without NaClO4 inhibition. Results: Fluorosulfate was identified as a potent inhibitor of 99mTc04 uptake via hNIS in vitro (half-maximal inhibitory concentration, 0.55-0.56 mu M (in comparison with 0.29-4.5 mu M for BF4-, 0.07 mu M for TcO4-, and 2.7-4.7 mu M for I-). Radiolabeling to produce F-18-SO3F- was simple and afforded high radiochemical purity suitable for biologic evaluation (radiochemical purity > 95%, decay-corrected radiochemical yield = 31.6%, specific activity >= 48.5 GE3q/mu mol). Specific, blockable hNIS-mediated uptake in HCT116-C19 cells was observed in vitro, and PET/CT imaging of normal mice showed uptake in thyroid, salivary glands (percentage injected dose/g at 30 min, 563 +/- 140 and 32 +/- 9, respectively), and stomach (percentage injected dose/g at 90 min, 68 +/- 21). Conclusion; Fluorosulfate is a high-affinity hNIS substrate. F-18-SO3F- is easily synthesized in high yield and very high specific activity and is a promising candidate for preclinical and clinical PET imaging of hNIS expression and thyroid-related disease; it is the first example of in vivo PET imaging with a tracer containing an S-F-18 bond.