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

Abstract

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 ¹²⁴I⁻ and ¹⁸F-BF₄⁻. We sought new ¹⁸F-labeled hNIS substrates offering higher specific activity, higher affinity, and simpler radiochemical synthesis than ¹⁸F-BF₄⁻. Methods: The ability of a range of anions, some containing fluorine, to block ^99mTcO₄⁻ uptake in hNIS-expressing cells was measured. SO₃F⁻ emerged as a promising candidate. ¹⁸F-SO₃F⁻ was synthesized by reaction of ¹⁸F⁻ 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 ^99mTcO₄⁻ 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 ¹⁸F-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 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. 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.