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 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.