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 124 I 2 and 18 F-BF 4 2 . We sought new 18 F-labeled hNIS substrates offering higher specific activity, higher affinity, and simpler radiochemical synthesis than 18 F-BF 4 2 . Methods: The ability of a range of anions, some containing fluorine, to block 99m TcO 4 2 uptake in hNIS-expressing cells was measured. SO 3 F 2 emerged as a promising candidate. 18 F-SO 3 F 2 was synthesized by reaction of 18 F 2 with SO 3 -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 (NaClO 4 ). PET/CT imaging and ex vivo biodistribution measurement were conducted on BALB/c mice, with and without NaClO 4 inhibition. Results: Fluorosulfate was identified as a potent inhibitor of 99m TcO 4 2 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 2 , 0.07 mM for TcO 4 2 , and 2.7-4.7 mM for I 2 ). Radiolabeling to produce 18 F-SO 3 F 2 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. 18 F-SO 3 F 2 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.

Cousins at work: How combining medical with optical imaging enhances in vivo cell tracking

“… Endogenously expressed in lthyroid, stomach, lacrimal, salivary and lactating mammary glands, small intestine, choroid plexus and testicles; tracers do not cross BBB. ( Dai et al, 1996 ; Jauregui-Osoro et al, 2010 ; Jiang et al, 2018 ; Khoshnevisan et al, 2017 , 2016 ) Transporter Norepinephrin transpo-rter (NET) PET: [ 124 I]MIBG, [ 11 C]hydroxyephedrine; SPECT: [ 123 I]MIBG. Endogenously expressed in organs with sympathetic innervation (heart, brain), tracers do not cross BBB.…”

Positron emission tomography reporter gene strategy for use in the central nervous system

“…The other PET reporter gene systems that have been used to monitor gene expression and gene therapy are not suitable for use in the CNS. These include herpes simplex virus type 1 thymidine kinase (HSV1-tk) (42) and its mutant (HSV1-sr38tk) (43), dopamine-2 receptor (D2R) (44) and its mutant (D2R80A) (45), type 2 cannabinoid receptor mutant (4), sodium iodide symporter (NIS) (46), and the somatostatin receptor 2 (47). Of these, only D2R80A and HSV1-tk have been used within the CNS, and only the latter in a clinical setting (48).…”

Rapid Aqueous Late‐Stage Radiolabelling of [GaF3(BnMe2‐tacn)] by 18F/19F Isotopic Exchange: Towards New PET Imaging Probes

“…Typically, radiofluorination is achieved by either converting a boronic ester moiety into a fluoroborate species or by an isotopic exchange reaction. Very recently, the development of [ 18 F]BF 4 − and [ 18 F]CF 3 SO 3 − as PET probes for imaging the sodium iodide symporter has been reported …”