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 124 I- and 18 F-BF4 - We sought new 18 F-labeled hNIS substrates offering higher specific activity, higher affinity, and simpler radiochemical synthesis than 18 F-BF4 - METHODS: The ability of a range of anions, some containing fluorine, to block 99m TcO4 - uptake in hNIS-expressing cells was measured. SO3 F- emerged as a promising candidate. 18 F-SO3 F- was synthesized by reaction of 18 F- 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. Radiotracer 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 99m TcO4 - uptake via hNIS in vitro (half-maximal inhibitory concentration, 0.55-0.56 μM (in comparison with 0.29-4.5 μM for BF4 - , 0.07 μM for TcO4 - , and 2.7-4.7 μM for I- ). Radiolabeling to produce 18 F-SO3 F- was simple and afforded high radiochemical purity suitable for biologic evaluation (radiochemical purity > 95%, decay-corrected radiochemical yield = 31.6%, specific activity ≥ 48.5 GBq/μmol). 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. 18 F-SO3 F- 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-18 F bond.