Research ArticleBasic Science Investigations

Synthesis of 18F-Tetrafluoroborate via Radiofluorination of Boron Trifluoride and Evaluation in a Murine C6-Glioma Tumor Model

Huailei Jiang, Aditya Bansal, Mukesh K. Pandey, Kah-Whye Peng, Lukkana Suksanpaisan, Stephen J. Russell and Timothy R. DeGrado
Journal of Nuclear Medicine September 2016, 57 (9) 1454-1459; DOI: https://doi.org/10.2967/jnumed.115.170894

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Abstract

The sodium/iodide symporter (NIS) is under investigation as a reporter for noninvasive imaging of gene expression. Although 18F-tetrafluoroborate (18F-TFB, 18F-BF4−) has shown promise as a PET imaging probe for NIS, the current synthesis method using isotopic exchange gives suboptimal radiochemical yield and specific activity. The aim of this study was to synthesize 18F-TFB via direct radiofluorination on boron trifluoride (BF3) to enhance both labeling yield and specific activity and evaluation of specific activity influence on tumor uptake. Methods: An automated synthesis of 18F-TFB was developed whereby cyclotron-produced 18F-fluoride was trapped on a quaternary methyl ammonium anion exchange cartridge, then allowed to react with BF3 freshly preformulated in petroleum ether/tetrahydrofuran (50:1). The resultant 18F-TFB product was retained on the quaternary methyl ammonium anion exchange cartridge. After the cartridge was rinsed with tetrahydrofuran and water, 18F-TFB was eluted from the cartridge with isotonic saline, passing through 3 neutral alumina cartridges and a sterilizing filter. Preclinical imaging studies with 18F-TFB were performed in athymic mice bearing NIS-expressing C6-glioma subcutaneous xenografted tumors to determine the influence of specific activity on tumor uptake. Results: Under optimized conditions, 18F-TFB was synthesized in a radiochemical yield of 20.0% ± 0.7% (n = 3, uncorrected for decay) and greater than 98% radiochemical purity in a synthesis time of 10 min. Specific activities of 8.84 ± 0.56 GBq/μmol (n = 3) were achieved from starting 18F-fluoride radioactivities of 40–44 GBq. An avid uptake of 18F-TFB was observed in human NIS (hNIS)–expressing C6-glioma xenografts as well as expected NIS-mediated uptake in the thyroid and stomach. There was a positive correlation between the uptake of 18F-TFB in hNIS-expressing tumor and specific activity. Conclusion: A rapid, practical, and high-specific-activity synthesis of the NIS reporter probe 18F-TFB was achieved via direct radiofluorination on BF3 using an automated synthesis system. The synthesis of high-specific-activity 18F-TFB should enable future clinical studies with hNIS gene reporter viral constructs.

The sodium/iodide symporter (NIS) is an intrinsic membrane glycoprotein, which mediates the uptake of iodide in the thyroid gland and other NIS-expressing cells or tissues (1–3). The active transport of iodide is the basis for the diagnosis and therapeutic treatment of thyroid disease and thyroid cancer. The clinical application of radioiodine also builds the foundation of modern nuclear medicine (4). The identification and characterization of human NIS (hNIS) in 1996 (5,6) created new opportunities for the use of hNIS as a reporter gene in viral therapy investigations and imaging of cell migration and differentiation. Despite considerable success in single-photon imaging of thyroid and thyroid cancers with 123I, 131I, or 99mTc-pertechnetate (2,3), there remain obvious limitations for use of these radioisotopes for diagnostic imaging. Both 123I (half-life [T1/2] = 13.13 h) and 131I (T1/2 = 8.02 d) are true iodine imaging radiotracers but have longer half-lives than required for a diagnostic study, which result in an unnecessarily high dose of irradiation to patients and staff. 99mTc-pertechnetate (T1/2 = 6 h) has found use as a radioiodine analog in thyroid diseases (7,8) and has suitable properties for SPECT. Nevertheless, SPECT has limited resolution and sensitivity, especially in detection of small metastases and low-volume diseases. PET has significantly better sensitivity and quantitative accuracy than SPECT, particularly for accumulations in small regions. The positron emitter 124I (T1/2 = 4.2 d) has been used in NIS imaging (9). However, the unnecessarily long half-life of 124I and its complex emission properties that include high-energy γ-photons are drawbacks for diagnostic imaging applications. Also, the production of 124I requires specialized solid target systems, which are not available in most cyclotron facilities (10). Positron-emitting 18F-fluoride (18F−, T1/2 = 109.7 min) is the most commonly used radioisotope for PET imaging. It has favorable physical decay properties of 97% positron emission and low positron energy (β+max = 0.635 MeV) and is produced by all PET cyclotrons. The development of 18F-fluoride–based PET tracers for NIS imaging would be encouraging. Because various anions (e.g., I−, SeCN−, SCN−, ReO4−, TcO4−, NO3−) are transported by NIS (6), the critical physicochemical feature of these well-transported substrates is anionic monovalency with size and space-filling properties similar to the iodide ion. Before the advent of clinical PET, in the1950s and early 1960s, Anbar et al. (11,12) reported that the tetrafluoroborate (TFB, BF4−) anion was effective to inhibit thyroid uptake of iodide ion. These researchers also showed that 18F-labeled TFB, synthesized from reactor-produced 18F-fluoride, specifically accumulated in rat thyroid. The initial labeling of TFB was accomplished by an ion exchange reaction of KBF4 in acid at room temperature or heating to make 18F-TFB, and the potassium salt was purified by recrystallization after neutralization (13). The isotopic exchange labeling approach inherently results in low-specific-activity 18F-TFB. Recently, Jauregui-Osoro et al. (14) updated the labeling of 18F-TFB using current 18F-fluoride production and purification methods. With the same mechanism, 18F-TFB was synthesized in a mixture of 1 mg of NaBF4 and 1.5N hydrochloric acid at 120°C. 18F-TFB of greater than 96% radiochemical purity was obtained in approximately 10% yield. The specific activity was approximately 1 GBq/μmol, with starting activities of 12–18 GBq of 18F-fluoride (14). PET/CT imaging in normal mice with transgenic thyroid tumors showed 18F-TFB to delineate uptake in normal tissues expressing NIS (thyroid, stomach, salivary glands) and enhanced uptake in thyroid tumor. Researchers from the same institution also showed that 18F-TFB was effective as a NIS probe in the NIS-transfected colon carcinoma cell line HCT116 (15). However, as pointed out by Youn et al. (16), specific activities achieved by the reported method are substantially lower than those typically required for receptor-mediated radiopharmaceuticals (∼30 GBq/μmol). In addition to this, a higher specific activity of 18F-TFB (>1 GBq/μmol) is desired to avoid pharmacologic effects of administered TFB on iodine uptake in the thyroid (14). Therefore, it is of interest to develop a synthesis of 18F-TFB with a higher specific activity. To perform PET imaging of NIS ultimately for clinical studies, our laboratory devoted efforts to synthesize high-specific-activity 18F-TFB via the reaction of boron trifluoride (BF3) and 18F-fluoride. We herein report a successful method that uses automation and a quaternary methyl ammonium (QMA) anion exchange cartridge as a solid phase support for this reaction.

MATERIALS AND METHODS

General

Lewatit MP-64 chloride form resin was procured from Sigma Aldrich and converted to carbonate form. Acetone, tetrahydrofuran, and BF3 were purchased from Sigma Aldrich. Petroleum ether was procured from Fisher Scientific. Sep-Pak Accell Plus QMA Carbonate Plus Light (46 mg of sorbent per cartridge, 40 μm particle size) and Alumina-N SepPak Light cartridges were obtained from Waters Corp. A Mini-scan radio–thin-layer chromatography (radio-TLC) scanner from Bioscan, Inc., was used to monitor the radiochemical purity. Anion high-performance liquid chromatography (HPLC) (IC-2100 [Dionex]; AS19 analytic column, 4.7 × 150 mm; eluent 35 mM potassium hydroxide; sample volume, 25 μL; flow rate, 1 mL/min) was calibrated to measure 19F-TFB and 18F-TFB concentrations with conductivity and radioactivity detectors in series. The method was validated by separation of a series of anions (F−, Cl−, Br−, I−, NO3−, CO32−, and BF4−), and OH− was negated by the system. Residual organic solvents were analyzed by gas chromatography (helium carrier gas flow at 10 mL/min through a MXT-WAX column [Restek; 0.53-mm inner diameter; 30-m length]). The temperature program was 4 min at 35°C, followed by a temperature ramp of 4°C per min to a maximum of 150°C.

18F-TFB Synthesis Method

An automated synthesis of 18F-TFB was developed for the preparation of 18F-TFB (Fig. 1). 18F-fluoride (37.6–40.5 GBq) was made by irradiation of 2.5 mL of 18O-water with 65 uA for 15 min in a PETtrace cyclotron (GE Healthcare) and then delivered to the hot cell and trapped on a QMA (46 mg, carbonate form) cartridge. 18O-enriched water was collected using valve V13. The QMA cartridge was rinsed with 10 mL of anhydrous acetone and flushed with nitrogen for 100 s. The freshly prepared BF3−petroleum ether/tetrahydrofuran (50:1) solution (5 mL; supplemental data [supplemental materials are available at http://jnm.snmjournals.org]; Fig. 1) was filtered by an in-house–made Lewatit MP-64 cartridge (200–400 mg; supplemental data; Fig. 2) and then passed through the QMA cartridge within 10 s to react with the trapped 18F-fluoride to form 18F-TFB. The QMA cartridge was rinsed with a solution of 10 mL of tetrahydrofuran, flushed for 100 s with nitrogen, and rinsed with 13 mL of water to further remove impurities. The crude 18F-TFB product was eluted from QMA with 5 mL of sterile 0.9% NaCl, U.S. Pharmacopeia solution (saline), and was further purified from unreacted 18F-fluoride by passing through 3 alumina-N SepPak Light cartridges. After passage through a 0.2-μM sterilizing filter, the 18F-TFB was collected in a product vial preloaded with an additional 5 mL of saline.

FIGURE 1.
FIGURE 1.

Schematic of automated module for preparation of 18F-TFB. Valves V1–V5 are composed of single-use cassette that is mounted to front of module. All other valves are nondisposable Teflon diaphragm solenoid valves.

FIGURE 2.
FIGURE 2.

Relationship of radiochemical yields (uncorrected) to amount of unlabeled BF4− produced as found using different amounts of MP-64 resin to prefilter the BF3-tetrahydrofuran/petroleum ether reagent (data from Table 1).

Quality Control

The product 18F-TFB was analyzed for radiochemical purity by both radio-TLC (MeOH, Rf = 0.8–0.85) and anion chromatography HPLC with a radioactivity detector (retention times, 3.7 min for 18F-fluoride, 7.8 min for 18F-TFB). Chemical purity, radiochemical identity, and specific activity were analyzed by anion chromatography HPLC (retention times, 3.5 min for fluoride, 4.3 min for chloride, 7.6 min for 19F-TFB [conductivity]). Residual organic solvents were analyzed by gas chromatography.

In Vivo Imaging

Studies with mice were performed under approval of the Mayo Clinic Institutional Animal Care and Use Committee. Dynamic PET was performed in hNIS-expressing C6-glioma xenografted athymic mice after retroorbital injection of approximately 1.1 MBq of Na 18F-TFB at different specific activities (10–0.001 mg of TFB/kg mouse) to assess hNIS activity with 18F-TFB. In this xenograft model, one flank had an hNIS-negative C6-glioma tumor xenograft, and the other flank had hNIS-expressing C6-glioma xenograft.

PET scans were acquired for 60 min followed by an x-ray scan using the GENISYS4 PET imaging system (Sofie Biosciences). The images from 40 hNIS-expressing C6-glioma xenografted mice were analyzed for SUV in the tumor, stomach, and thyroid using AMIDE image processing software (17). The SUV in the tumor was normalized with SUV in the stomach to account for difference in 18F-TFB bioavailability in different animals due to competing uptake in normal organs such as thyroid, salivary glands, and stomach.

Immunohistochemistry

Tumors from 5 age-matched hNIS-expressing C6-glioma xenografted mice were harvested and formalin-fixed. The tumors were then equilibrated in 15% and 30% sucrose with phosphate buffer for 4 d, and frozen for cryosectioning. A series of adjacent sections were cut on a cryostat. Each section was 10-μm thick and mounted onto charged slides (Superfrost Plus slides; Fisherbrand). After being dried, the sections were blocked with 10% goat serum for 4 h at room temperature, followed by overnight incubation with 1:4,000 dilution of rabbit antihuman NIS antibody SJ1 (Imanis Life Sciences) in phosphate-buffered saline (PBS) with 10% goat serum at 4°C. The sections were rinsed 3 times in PBS-polysorbate 20 (0.05%) for 15 min each at room temperature. The sections were incubated with secondary antibody, Alexa Fluor 488 goat antirabbit IgG (H + L) antibody (Life Technologies), at a dilution of 1:4,000 in PBS for 45 min at room temperature. Following incubation with secondary antibody, the sections were rinsed 3 times in PBS-polysorbate 20 (0.05%) for 15 min each at room temperature. Subsequently, the sections were counterstained with nuclear stain, 4′,6-diamidino-2-phenylindole (DAPI). The sections were then cover-slipped with mounting medium and imaged using a Nikon Eclipse Ti inverted microscope at 10× magnification.

Data Analysis and Statistics

Data are mean ± SD. MicroSoft Excel Solver was used to regress the tumor-to-stomach ratios of 18F-TFB uptake using a nonlinear least-squares regression algorithm.

RESULTS

Radiosynthesis and Quality Control of 18F-TFB

18F-TFB was successfully produced by radiofluorination of BF3 by passing a BF3-containing solution through a QMA cartridge preloaded with 18F-fluoride and dried with acetone and nitrogen. The amount of starting BF3 for the reaction was found to be critical to determine both the radiochemical yields and the specific activities. First, 5 mL of BF3-tetrahydrofuran/petroleum ether solution (∼45 μmol) were used in the reaction, and 8.33 ± 0.65 μmol unlabeled TFB with 35.0% ± 3.6% yields were obtained. To decrease the amount of BF3 for the reaction, the BF3-tetrahydrofuran/petroleum ether solution was passed through Lewatit MP-64 resin immediately before passage through the QMA cartridge. Lewatit MP-64 is an anion exchange resin, which contains cross-linked polystyrene matrix with tertiary amine and quaternary ammonium functional groups. Separate analysis of the post-Lewatit MP-64 filtrate showed that 70%, 80%, and 90% of the BF3 in the original 5 mL of BF3-tetrahydrofuran/petroleum ether solution were retained on 200, 300, and 400 mg of Lewatit MP-64 resin, respectively. Thus, Lewatit MP-64 resin effectively reduced the amount of BF3 reactant available for the reaction. Investigations with 200–400 mg of Lewatit MP-64 resin (Table 1) resulted in the production of unlabeled TFB and product 18F-TFB in proportional amounts (Fig. 2). Thus, the specific activity of the 18F-TFB product improved as the amount of Lewatit MP-64 resin was increased, however, at the cost of decreased radiochemical yield.

View this table:
TABLE 1

Dependence of Overall Radiochemical Yield and Specific Activity (n = 3) of 18F-TFB Product on Amount of Lewatit MP-64 Resin

We chose to use 300 mg of Lewatit MP-64 resin for a high-radioactivity-level synthesis (40–44 GBq) as a compromise between radiochemical yield and specific activity. The radiochemical yield of 18F-TFB was 20.0% ± 0.7% (n = 3) uncorrected in a synthesis time of 10 min. Radiochemical purity was greater than 98% as shown on silica gel radio-TLC (supplemental data; Fig. 3) and anion chromatography HPLC (Fig. 3). Specific activities of 8.84 ± 0.56 GBq/μmol (n = 3) were achieved from starting 18F-flouride activities of 40–44 GBq.

FIGURE 3.
FIGURE 3.

HPLC analysis of 18F-TFB product in saline. (A) Conductivity data for 10 μg/mL NaF standard. (B) Conductivity data for 10 μg/mL NaBF4 standard. (C) Radioactivity data for 1.1 MBq of 18F-fluoride standard. (D) Conductivity data for purified 18F-TFB in saline. (E) Radioactivity data for purified 18F-TFB in saline.

Residual acetone and tetrahydrofuran were obtained in concentrations of 63–135 and 24–27 ppm (supplemental data; Fig. 4), respectively, which were well under the allowed solvent concentration limits (acetone, 5,000 ppm; tetrahydrofuran, 720 ppm) set by the International Conference on Harmonization for technical requirements for registration of pharmaceuticals for human use.

FIGURE 4.
FIGURE 4.

Time dependence of 18F-TFB uptake (SUV) in different organs in representative hNIS-expressing C6-glioma xenografted mice at high specific activity of 18F-TFB (13 MBq/μmol or 0.37 mg/kg mouse weight) (A) and low specific activity of 18F-TFB (3 MBq/μmol or 1.6 mg/kg mouse weight) (B).

Stability of 18F-TFB

Production samples stored for longer than 20 h at room temperature showed radiochemical purities greater than 96% on radio-TLC and HPLC. A slow release of 18F-fluoride was observed, presumably reflecting a slow hydration of 18F-TFB. HPLC analysis of a NaBF4 stock solution stored for 7 mo at room temperature showed 50% of TFB had converted to fluoride.

In Vivo Imaging Studies

Robust uptake of 18F-TFB was observed in the thyroid, stomach, bladder, and hNIS-expressing tumors of the C6-glioma xenograft mouse model (Figs. 4 and 5). No uptake of 18F-TFB was observed in hNIS-negative tumors, confirming specificity of uptake of 18F-TFB to hNIS-expressing tumors. 18F-TFB uptake in the thyroid and hNIS-expressing tumor showed a biphasic kinetic: rapid uptake over the first 10 min was followed by slower uptake until 30 min with little subsequent change. The stomach showed linear increase in 18F-TFB uptake over 60 min. Stomach uptake was independent of specific activity of 18F-TFB whereas uptake in hNIS-expressing tumor and thyroid was dependent on specific activity of 18F-TFB. The uptake of 18F-TFB by hNIS-expressing tumor was higher at high specific activity (>13 MBq/μmol) than lower specific activity (3 MBq/μmol). This trend was also seen for the thyroid. No evidence of bone uptake of 18F radioactivity was seen, corroborating previous findings of negligible in vivo defluorination of 18F-TFB in mice (14).

FIGURE 5.
FIGURE 5.

PET images of 18F-TFB distribution at 60–70 min in control mouse (left) and mouse bearing hNIS-positive and hNIS-negative C6-glioma xenografts. Overlaid reference bone atlas is computer generated. Bl = bladder; St = stomach; Th = thyroid.

For a more detailed analysis of the effect of specific activity of 18F-TFB on uptake in hNIS-expressing tumors, a 60-min time point was chosen, and a range of specific activities (10–0.001 mg of TFB injected/kg mouse weight) was tested. The uptake in tumor was normalized to stomach uptake to account for differences in bioavailability of 18F-TFB across animals. The uptake of 18F-TFB in hNIS-expressing C6 tumor showed dependence on specific activity at 10–0.5 mg of TFB/kg of mouse weight or 0–10 MBq/μmol considering approximately 1.1-MBq radioactivity injected in approximately 25-g mice. But this trend was not observed for higher specific activities (>10 MBq/μmol TFB or < 0.5 mg TFB/kg mouse weight) (Fig. 6). At these higher specific activities, the uptake of 18F-TFB was no longer dependent on specific activity but exhibited high variability. Immunohistochemistry analysis for hNIS in tumor sections from 5 mice showed significant intratumoral and intertumoral variability of expression of hNIS (Fig. 7) that may play a role in the variability of 18F-TFB uptake observed in tumors.

FIGURE 6.
FIGURE 6.

Dependence of tumor (A), stomach (B), and tumor-to-stomach ratio (C) of 18F-TFB uptake at 60–70 min on administered mass of TFB to hNIS-expressing C6-glioma xenografted mice. Tumor-to-stomach ratio data for administered mass greater than 0.5 mg/kg was fit to biexponential clearance model using nonlinear least-squares regression.

FIGURE 7.
FIGURE 7.

Immunostaining of hNIS-expressing C6-glioma xenografts (10× magnification) showing intratumoral and intertumoral variability of expression of hNIS. Blue = DAPI-stained nucleus; green = Alexa Fluor 488 antibody–bound hNIS.

DISCUSSION

It has been proposed that the 18F-labeled iodide analog 18F-TFB may have high utility as an hNIS gene reporter probe for PET studies (14); however, the existing isotope exchange labeling method rendered the product with moderate specific activity. Because BF3 is known to form TFB in the presence of water via a fluoride exchange reaction (18,19), we aimed to use this reaction to prepare high-specific-activity 18F-TFB. By the new methodology, specific activities of 8.84 ± 0.56 GBq/μmol and uncorrected radiochemical yields of 20.0% ± 0.7% were obtained with a starting activity of 40–44 GBq. Further modifications of the method can produce even higher-specific-activity 18F-TFB at the sacrifice of radiochemical yield, or higher radiochemical yield at the sacrifice of lower specific activity (Table 1). The highest specific activity obtained by acid-catalyzed 18F-fluoride exchange on TFB was approximately 1 GBq/μmol, with starting activities of 12–18 GBq of 18F-fluoride, and the radiochemical yield was approximately 10% (14).

Jauregui-Osoro et al. (14) estimated that the administration of approximately 400 MBq of 18F-TFB synthesized by the conventional method to a human subject would result in a plasma concentration of approximately 0.1 μM TFB. Considering the half maximal inhibitory concentration (IC50) of TFB to be 0.1–1 μM for inhibition of iodine uptake by NIS in the thyroid (20), it is desirable to increase 18F-TFB specific activity above approximately 5 GBq/μmol to avoid a pharmacologic effect (14). The presently reported synthesis method for 18F-TFB achieves this goal. At a specific activity of 8 GBq/μmol, an approximately 400-MBq administered dose of 18F-TFB would give an estimated in vivo concentration of approximately 0.02 μM TFB, which should not exhibit a pharmacologic effect.

To evaluate the influence of 18F-TFB specific activity on in vivo uptake by NIS-expressing tissues, we used an hNIS-expressing C6 tumor xenograft mouse model. As expected, 18F-TFB was taken up by selected organs expressing NIS in the xenograft mouse model. Among the select organs, thyroid and hNIS-expressing tumor were sensitive to a specific activity of 18F-TFB as 18F-TFB was being transported using NIS in these organs. On the other hand, in the stomach, which also possesses NIS (21–23), the uptake of 18F-TFB was found to be independent of its specific activity. The insensitivity of 18F-TFB uptake to specific activity in the stomach was not clarified but may point to different kinetic properties of the NIS protein in gastric mucosal cells as compared with thyroid and hNIS-expressing tumor (22,23). Another possible explanation is that 18F-TFB entering the gastric epithelial cells is immediately effluxed into the stomach lumen such that the intracellular concentration (e.g., in gastric parietal cells) is never in equilibrium with the interstitial fluid so unidirectional transport continues unabated. A biphasic response was observed in hNIS-expressing tumor uptake of 18F-TFB versus administered dose of unlabeled TFB. The 18F-TFB uptake in tumor decreased with increasing amount of administered TFB over the range of 0.5–10 mg TFB/kg of mouse weight, but this trend was not observed for higher specific activities (<0.5 mg TFB/kg of mouse weight). Rather, the tumor uptake was constant but highly variable for administered TFB doses of less than 0.5 mg/kg. The reason for this trend is not clear, but it is possible that at high specific activity, factors other than specific activity contribute to the variability, such as variability in the inter- and intratumoral expression or activity of hNIS, number of tumor cells expressing hNIS, heterogeneity of tumor perfusion or oxygenation, variability of tumor size, or the indirect influence of differences in the physiologic distribution of radiotracer to other areas of the body. The large variation seen in hNIS expression levels in the C6-glioma xenografts may reflect the fact that the C6-hNIS–transduced cell line was not a clonal population but included high-, low-, and negative-expressing cells. The ability of the 18F-TFB PET method to reliably report on viral infection depends on hNIS expression within infected cells and possibly posttranslational events that influence hNIS transporter activity (24). These considerations must also be kept in mind for future studies in monitoring hNIS transduction in human studies that may also entail significant heterogeneity of hNIS expression after viral therapies. Nonetheless, it was encouraging to observe a broad range of specific activities of 18F-TFB over which tumor uptake was robust.

CONCLUSION

A solid-phase supported synthesis of 18F-TFB was developed via radiofluorination of BF3. With the optimized condition, the radiochemical yield of 18F-TFB was 20.0% ± 0.7% (n = 3) uncorrected in a synthesis time of 10 min. Specific activities of 8.84 ± 0.56 GBq/μmol (n = 3) were achieved with starting 18F-fluoride radioactivities of 40–44 GBq. A positive correlation was observed between specific activity of 18F-TFB and hNIS-expressing C6-glioma xenografts for lower specific activities resulting in administration of TFB exceeding 0.5 mg/kg in mice. The increased specific activity of 18F-TFB may allow for enhanced PET imaging of hNIS reporter in future human studies.

DISCLOSURE

The costs of publication of this article were defrayed in part by the payment of page charges. Therefore, and solely to indicate this fact, this article is hereby marked “advertisement” in accordance with 18 USC section 1734. The work was supported by the Department of Radiology, Mayo Clinic. No other potential conflict of interest relevant to this article was reported.

Acknowledgments

We thank Benjamin C. Jager for the analysis of PET images and Ping Fang for the support of 18F-fluoride production and gas chromatography analyses.

Footnotes

  • Published online Apr. 21, 2016.

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  • Received for publication December 11, 2015.
  • Accepted for publication March 14, 2016.
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