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 ¹²⁴I2 and ¹⁸F-BF⁴². We sought new ¹⁸F-labeled hNIS substrates offering higher specific activity, higher affinity, and simpler radiochemical synthesis than ¹⁸F-BF⁴². Methods: The ability of a range of anions, some containing fluorine, to block ^99mTcO⁴² uptake in hNIS-expressing cells was measured. SO₃F-emerged as a promising candidate. ¹⁸F-SO₃F₃ was synthesized by reaction of ¹⁸F-with SO^-3pyridine 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 ^99mTcO^-4 uptake via hNIS in vitro (half-maximal inhibitory concentration, 0.55-0.56 mM (in comparison with 0.29-4.5 mM for BF^-4, 0.07 mM for TcO^-4, and 2.7-4.7 mM for I₂). Radiolabeling to produce ¹⁸F-SO₃F₂ was simple and afforded high radiochemical purity suitable for biologic evaluation (radiochemical purity . 95%, decay-corrected radiochemical yield 5 31.6%, specific activity ≥48.5 GBq/mmol). 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 6 140 and 32 6 9, respectively), and stomach (percentage injected dose/g at 90 min, 68 6 21). Conclusion: Fluorosulfate is a high-Affinity hNIS substrate. ¹⁸F-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-¹⁸F bond.