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Clinical Investigations |
Departments of Radiology, Chemistry, Surgery, Pediatrics, and Radiation Safety, Duke University Medical Center, Durham, North Carolina
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ABSTRACT |
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 TOP ABSTRACT INTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONCONCLUSIONREFERENCES |
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Key Words: choline • PET • prostate cancer • breast cancer • brain tumors
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INTRODUCTION |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONCONCLUSIONREFERENCES |
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11C-Labeled choline (trimethyl-2-hydroxyethylammonium) (Fig. 1) (half-life = 20 min) has shown potential usefulness in 3 applications: brain tumors (4,5), for which FDG has suboptimal specificity because of uptake by normal brain and some posttherapy responses (6); prostate carcinoma (7), for which FDG has inadequate sensitivity (3,8); and esophageal carcinoma (9), for which background activity with FDG limits detection of neoplasms in the mediastinum. The practical advantages of working with the longer-lived radioisotope 18F (half-life = 110 min) led Hara et al. (10) to synthesize and preliminarily evaluate the choline analog 2-[18F]fluoroethyl-dimethyl-2-hydroxyethylammonium (FEC) (Fig. 1). We recently reported the synthesis and preliminary evaluation of no-carrier-added [18F]fluorocholine (fluoromethyl-dimethyl-2-hydroxyethylammonium [FCH]) as a PET probe of prostate cancer (11) (Fig. 1). On the basis of structural similarity, we anticipated that the [18F]fluoromethylated FCH would mimic choline transport and metabolism more closely than that of the [18F]fluoroethylated FEC, resulting in physiologic processing closer to that of choline. In this study, the uptakes of FCH, FEC, and other structurally similar choline analog tracers were evaluated for their biologic acceptance for phosphorylation by choline kinase (CK) and uptake by cultured PC-3 human prostate cancer cells. Preliminary data on chemical stability, toxicity, and radiation dosimetry for FCH are reported. Finally, FCH PET was performed on a patient with prostate cancer and a patient with a brain tumor.
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MATERIALS AND METHODS |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONCONCLUSIONREFERENCES |
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The radiochemical purity of the 18F-labeled choline analogs was monitored by cation-exchange HPLC as described for measurement of CH metabolites (13). The column was Partisil SCX (250 x 4.6 mm; Alltech Associates) eluted by 0.25 mol/L sodium dihydrogen phosphate solution (pH 4.8) and acetonitrile (90:10) at a flow rate of 1.8 mL/min. Radioactivity and ultraviolet absorbance (206 nm) of the eluent were measured in series. The retention times were 5.0, 5.4, 5.5, and 6.0 min for FCH, FEC, FMEC, and FPC, respectively (Fig. 2). The cation-exchange HPLC system was found to be preferable to the reverse-phase HPLC system originally developed for quality assurance of FCH (11) because peak resolution was superior, and retention of radioactivity on the column was negligible.
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Stability of FCH
The stability of FCH in its prepared form was evaluated by monitoring the radiochemical purity using the HPLC system described above. Furthermore, the stability of FCH in blood was examined by incubating approximately 3.7 MBq FCH in a 3-mL sample of heparinized whole blood taken from healthy human subjects (n = 5). After a 2-h incubation at 37°C, the plasma was separated, the plasma proteins were precipitated by adding 2 volumes of methanol, and the supernatant was analyzed for intact FCH by cation-exchange HPLC.
Analysis of Hydrophilic Choline or FCH Metabolites in Biologic Samples
The primary hydrophilic metabolites of choline in mammals are phosphocholine and betaine. If FCH is handled similarly biochemically to CH in cancer cells, then 18F-labeled phosphorylfluorocholine (P-FCH) and fluorobetaine (FB) may be formed. To measure the levels of FCH, FB, and P-FCH in biologic samples, a modification of the gradient-HPLC method of Pomfret et al. (14) was used. 14C-Labeled betaine and phosphocholine were prepared enzymatically from commercially available CH (NEN Research Products) using choline oxidase (13) and CK (15), respectively. The HPLC system used a microprocessor-controlled solvent delivery system and a silica column (Adsorbosphere silica [10 µ], 250 x 4.6 mm; Alltech Associates). The column was kept at room temperature and the flow rate was maintained at 1.5 mL/min. Buffer A contained acetonitrile, ethanol, acetic acid, 1.0 mol/L ammonium acetate, water, and 0.1 mol/L sodium phosphate (800:68:2:3:127:10 [v/v]) and buffer B contained the same constituents but in different proportions (400:68:44:88:400:10 [v/v]). Fractions of effluent were collected every 0.5 min and counted first for 18F radioactivity in a well counter for experiments involving FCH and then transferred to scintillation vials for counting 14C radioactivity. The column was equilibrated for 6 min with buffer A before injection. After the injection (<100 µL), buffer A was delivered for 6 min, which eluted betaine (3 min) from the column. Over a period of 10 min, solvents were switched to 100% buffer B using a linear gradient, during which time FCH (12.5 min) and choline (15 min) were eluted. Buffer B was then delivered for a further 9 min, eluting phosphocholine (19.5 min). Reequilibration of the column with 100% buffer A for 6 min preceded the next injection.
In Vitro Phosphorylation of FCH by Yeast CK
To determine whether FCH is a substrate for CK, FCH (0.9–1.8 MBq) and CH (74–150 kBq) were incubated in a test tube with yeast CK (25 milliunits [mU]/mL), choline (1–10,000 µmol/L), MgCl2 (12.5 mmol/L), and ATP (10 mmol/L) in Tris . HCl buffer (0.1 mol/L, pH 8.75) for 10 min at 23°C. The test tube was gently agitated throughout the incubation period. Tubes were placed in a boiling water bath for 2 min to stop the reaction. To serve as controls, some samples were placed directly in the boiling water bath after addition of all substrates. The phosphorylated fraction of each radiotracer was isolated from the nonmetabolized fraction by anion-exchange chromatography according to the method of Ishidate and Nakazawa (15) and counted in a well counter or a scintillation counter. The percentage of radioactivity converted to the phosphorylated form was calculated. Preliminary studies showed the phosphorylated fraction to rise linearly with time for incubations of <15 min.
Uptake and Metabolism of Radiotracers by PC-3 Human Prostate Cancer Cells
Cells (2.5 x 105 per well) were seeded on 6-well plates and incubated for 2 d, at which time >90% confluence was reached. The incubation medium was Dulbecco’s modified Eagle’s medium (DMEM) supplemented with 10% calf serum. The medium contained 15 mmol/L glucose. On the day of the study, the medium was refreshed using a volume of 1 mL in each well. Cells were incubated under control conditions or with the addition of metabolic and growth factor receptor inhibitors to test the sensitivity of uptake of the radiotracers to specific inhibition. The inhibitor of choline uptake and phosphorylation, hemicholinium-3 (HC-3) (Research Biochemicals, Natick, MA), was added to give a concentration of 5 mmol/L. The concentration of the inhibitor was approximately 10 times the literature in vivo inhibitory concentration of 50% (IC50) for choline phosphorylation (16). After a 30-min incubation period, the radiotracers were added (
74 kBq per well) in separate wells and the cells were incubated at 37°C for 2 h. The radioactive medium was removed and the cells were washed 3 times with phosphate-buffered saline solution, released from the plates by incubating briefly with 0.05% trypsin in DMEM, transferred to test tubes, and counted for radioactivity in a 
-counter (18F) or a liquid scintillation counter (14C). The amount of radioactivity in the cells was normalized by the dose administered to each well.
Preliminary analysis of radiolabeled metabolites of FCH and CH in PC-3 cells was performed. Cells were incubated in 6-well plates with a mixture of FCH (3.7 MBq) and [14C]CH (74 kBq) for 2 h as described above, followed by removal of radioactive medium and 3 rinses with phosphate-buffered saline solution. Methanol (1 mL) was added to each well and the cells were lysed by maintaining the temperature at 37°C for 30 min. The methanol phase was transferred to a glass test tube. Each well was rinsed with an additional 0.5 mL methanol that was added to the original fraction. To each tube, 3 mL chloroform and 1 mL 0.25 mol/L sodium phosphate (pH 4.5) were added to separate lipids from water-soluble molecules. After vigorous mixing of the samples for 1 min, the 2 phases were separated, and a 0.5-mL aliquot of each phase was counted for 18F and 14C radioactivity. The aqueous phase was further analyzed for water-soluble metabolites using the gradient-HPLC method described earlier. Radioactivity in the metabolite fractions (lipid, CH/FCH, [14C]-betaine/FB, [14C]-phosphocholine/P-FCH) was expressed as the percentage of total radioactivity administered to each well.
Human Dosimetry Estimation
Tissue distribution data (percentage dose per gram of tissue) obtained in a mouse model after injection of FCH (11) were converted to the percentage dose per organ using the method of Kirschner et al. (17). The distribution was assumed to be static at >10 min after injection, consistent with the long retention of the tracer in tissue (11). These data were entered into the MIRDOSE 3.1 program (18) to calculate dose estimates. Urinary radioactivity was assumed to be retained within the urinary bladder. Thus, assumptions made in these calculations would tend to overestimate the radiation dose in human imaging studies in which urinary radioactivity may be voided after the imaging study is performed. Because urinary excretion patterns in rodents are commonly more rapid than those in humans, the assumption of no urinary clearance of radioactivity was precautionary. Bone uptake was distributed at the bone surfaces. The look-up table corresponding to a 70-kg adult male Oak Ridge National Laboratory phantom was used because this would best reflect the primary study population (prostate carcinoma).
Toxicity Study
Four unanesthetized BALB/c nude mice were administered 1 mg/kg [19F]FCH through tail vein injection and monitored for 48 h. This dose represented an approximately 300,000-fold excess of FCH in comparison with the normal dose that a 70-kg person would receive in a FCH PET study. The mice were killed at 48 h.
PET Studies
The biodistribution of FCH was investigated in a patient with prostate cancer, a patient with metastatic breast cancer, and a patient with a brain tumor. The FCH PET studies were approved by the Duke University Medical Center Institutional Review Board and Cancer Research Committee. The subjects were informed of all risks associated with the study and written informed consent was obtained. Patient 1 had undergone prostatectomy and radiation therapy and was being evaluated for recurrence of prostate cancer. Patient 2, having previously undergone resection of an astrocytoma, was also being evaluated for recurrence of disease. Patient 3 was a 50-y-old breast cancer patient who had undergone mastectomy 3 y earlier, followed by tamoxifen chemotherapy. Imaging was performed using an Advance PET scanner (General Electric Medical Systems, Milwaukee, WI) with an intrinsic spatial resolution of 5 mm in all directions (19). A transmission scan of the pelvic region was obtained before administration of radiotracer. [18F]FCH (93–185 MBq) was administered intravenously. In the first patient dynamic imaging of the lower pelvic region commenced for 10 min (frame sequence = 12 x 10 s, 8 x 1 min). After the dynamic scan, a whole-body emission scan (4 min per bed position) was obtained without attenuation correction. In the patient with a brain tumor, a 4-min transmission scan of the head preceded the injection of radiotracer. For the breast cancer and brain tumor patients, FDG PET images were acquired within 1 wk of the FCH PET scan. Approximately 370 MBq FDG were administered intravenously, and emission imaging commenced at 45 min after injection. The emission imaging of the brain was performed in 3-dimensional scanning mode (septa out), whereas imaging of the body was performed in 2-dimensional mode (septa in). The images were reconstructed using an ordered subset expectation maximization algorithm. Regions of interest (ROIs) were drawn manually on the attenuation-corrected images for evaluation of FCH kinetics in tissues. Standardized uptake values (SUVs) of FCH uptake in tissues were calculated using the attenuation-corrected images according to the equation:
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Statistical Methods
Results are expressed as mean ± SD. Statistical analysis was performed using the Student t test, and statistical significance was inferred at P < 0.05.
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RESULTS |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONCONCLUSIONREFERENCES |
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In Vitro Phosphorylation of FCH by Yeast CK
To determine whether FCH is a substrate for CK, FCH and [methyl-14C]choline (CH) were incubated with yeast CK (25 mU/mL) and choline (1–10,000 µmol/L) for 10 min at 23°C. Samples quenched by boiling before incubation showed negligible phosphorylation activity. Figure 3 shows that, after separation from unreacted FCH and CH using an anion-exchange resin (15), a single, more polar chemical product is formed from FCH and CH. The 14C-labeled product exhibited the same retention time as an authentic standard for unlabeled phosphocholine, seen by in-series ultraviolet detection. The presence of a single 18F-labeled product and the similar relationship of retention times between FCH and CH (Fig. 3A) and their phosphorylated products (Fig. 3B) suggest that the 18F-labeled product is P-FCH. Figure 4 shows the dependence of phosphorylation rate on choline concentration, displaying a similar sigmoid relationship for both radiotracers that is typical of Michaelis–Menten-type kinetics. The apparent IC50 values for inhibition of phosphorylation of radiotracer by choline were 0.4 mmol/L for FCH and CH. The phosphorylation rates were similar for FCH and CH at all choline concentrations. At a low choline concentration of 1 µmol/L, phosphorylation rates of FCH and FMEC were equivalent to that of CH, whereas phosphorylation rates of FEC and FPC were approximately 30% and 60% less than that of FCH, respectively (Table 1).
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Analysis of Metabolites of FCH and [14C]CH in Cultured PC-3 Prostate Cancer Cells
A preliminary analysis of the chemical form of radioactivity present in PC-3 cells incubated with FCH and CH was performed. Cells incubated in 6-well plates for 2 h with radiotracers were washed thoroughly to remove all extracellular radioactivity. The cells were lysed in methanol, and the methanol solution was added to chloroform to solubilize all lipophilic metabolites. The hydrophilic metabolites were extracted with 0.25 mol/L sodium phosphate solution (pH 4.8) and subjected to gradient-HPLC analysis for measurement of radioactivity in the form of FCH/CH, FB/betaine, and P-FCH/phosphocholine. Table 2 shows the results expressed as percentage of administered dose to each well. CH and FCH were found to undergo extensive metabolism within the PC-3 cells. Approximately 72% of 18F radioactivity was indicated to be P-FCH, whereas 91% of 14C radioactivity was found as [14C]phosphocholine (Table 2; Fig. 3). Radiolabeled lipophilic metabolites of FCH comprised 25% of the total 18F radioactivity, whereas lipophilic metabolites of CH represented only 7% of the total 14C radioactivity. A 5-fold higher incorporation of radioactivity into lipophilic species for FCH was found relative to CH. Neither [14C]betaine nor its 18F-labeled counterpart was detected by HPLC analysis, indicating that oxidation of FCH and CH in the cancer cells was negligible.
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74 GBq/µmol), the normal dose of FCH in the radiotracer preparation would be a factor of 300,000 times lower than the dose given in this toxicity study.
PET in Patients
Patient 1.
A 66-y-old man was initially diagnosed 5 y earlier with locally advanced clinical stage T3 N0 M0 prostate cancer and underwent radical prostatectomy followed by external beam radiation to the prostate bed. His serum prostate-specific antigen (PSA) was 2.0 ng/mL after therapy. The patient then underwent androgen-deprivation therapy. Because his serum PSA began rising at approximately 1 y before PET scanning, the chemotherapy was discontinued. The current serum PSA of the patient was 40.1 ng/mL. Recent radionuclide bone scans showed no abnormalities, whereas CT of the chest, abdomen, and pelvis showed only small lymph nodes (1 cm) in the pelvis and mediastinum. FCH PET images acquired at 2–4 min revealed accumulation of FCH in the prostate bed before the arrival of activity at the bladder (Fig. 5A). Figure 5B shows the kinetics of FCH in the prostate bed and ROIs drawn within the urinary bladder and iliac artery. The arterial concentration of FCH peaked early and fell rapidly to <5% of the peak level within 2 min after injection, indicating extremely rapid blood clearance. Radioactivity concentration rose rapidly in the prostate bed and reached a plateau by 3 min after injection. Radioactivity began to arrive in the bladder at 4–5 min after injection and the concentration increased rapidly thereafter. The whole-body images showed abnormally high foci of FCH uptake in the chest suggestive of prostate cancer within mediastinal lymph nodes (Fig. 5C).
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10:1 and was attained within 5 min after injection. Most, but not all, of the FCH-avid regions corresponded with Gd-enhanced regions on the MR images. Biopsies taken from the cavity wall confirmed recurrence of the tumor. The FDG PET images indicated a thin rim of increased FDG uptake located posteriorly on the cyst wall, but the boundary of the tumor could not be reliably determined because of high uptake of FDG by normal cortex.
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5.5), and the pelvic tumor (SUV, 9.5) (Fig. 7). Uptake of FCH was also observed in the corresponding tumors: sternal mass (SUV, 14.6), mediastinal and hilar adenopathies (SUVs, 8.5), and pelvic mass (SUV, 6.5). The parasternal mass appeared significantly larger on the FCH PET scan relative to that on the FDG PET scan. Smaller metastases were indicated on the FCH PET scan in the right chest wall and left lung that were not seen on the FDG PET scan. In reference to the anterior pelvic tumor, a homogeneous distribution of FDG was observed across the tumor in the FDG PET scan, whereas the FCH was preferentially distributed on the periphery of the tumor.
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DISCUSSION |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONCONCLUSIONREFERENCES |
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Positron-labeled cholines, as first pioneered by Hara’s research group (4,5,7,9) using 11C as radiolabel and further advanced by our group with introduction of the N-[18F]fluoromethyl labeling group (11), appear to have several favorable properties as oncologic PET probes. First, the pathophysiology of choline processing in malignant tissues is well established (20–25). Extensive studies using MR spectroscopy (20) and biochemical analyses (21–25) have revealed elevated levels of choline, phosphocholine, and phosphoethanolamine in many types of cancer cells in consort with enhanced synthesis rates of membrane phospholipids. The activity of CK has been found to be upregulated in malignant cells (22–25), providing a potential mechanism for the enhanced accumulation of radiolabeled choline analogs by neoplasms. These findings have motivated the development of MR spectroscopic imaging techniques for mapping of choline levels in prostate cancer (26,27) and brain tumors (28,29). Second, the rapid and extensive clearance of radiolabeled cholines from the blood after intravenous administration allows commencement of PET of cancer early (2–3 min) after bolus injection of radiotracer. Third, [11C]choline (7) and FCH (11) allow assessment of neoplasms in the pelvis before arrival of radioactivity at the urinary bladder. Finally, the uptake of positron-labeled cholines is very low in normal tissues of the cerebral cortex, lung, heart, bone, and skeletal muscle, allowing excellent differentiation of malignancies against these tissues. Detection of malignant adenopathies in the chest is enhanced by low uptake in the lung, heart, and mediastinum (9).
Our results indicate that FCH closely mimics choline in its in vitro phosphorylation by yeast CK and uptake and metabolism in cultured human prostate cancer cells. A human CK complementary DNA has been cloned by complementation of the yeast CK mutation, cki, from a human glioblastoma complementary DNA expression library (30). The human enzyme was found to resemble the rat liver enzyme over the entire sequence. It also resembled the yeast enzyme in the carboxyl-terminal region, which is thought to be involved in the catalytic function of the enzyme (30). Thus, our results with yeast CK are likely representative of properties of human CK. Further support for the acceptance of FCH by CK is found in the analytic studies of 18F radioactivity after incubation of FCH in cultured PC-3 human prostate cancer cells. After incubation of FCH under control conditions, nearly all 18F radioactivity in the cancer cells is associated with a polar metabolite fraction that exhibits the same HPLC retention time as the single product of in vitro incubations of FCH with CK (Fig. 3). The identity of this metabolite was accordingly assigned as P-FCH, although an independent chemical synthesis of P-FCH is desirable for further validation of the analytic results. The apparent IC50 values for inhibition of FCH and CH in vitro phosphorylation by unlabeled choline of 0.4 mmol/L are high relative to the normal range of choline concentrations in the plasma (0.01–0.1 mmol/L) (31). Pretreatment of cultured PC-3 human prostate cancer cells with 5 mmol/L HC-3, an inhibitor of choline transport and phosphorylation (16,32), resulted in a >90% decrease in FCH accumulation, evidencing the specificity of FCH for the choline processing pathway. The higher incorporation of FCH relative to [14C]choline into lipophilic metabolites in PC-3 cells was a surprising result that requires further investigation.
FCH differs from FEC by a single methylene group between the nitrogen atom and the carbon bearing the fluorine atom. Remarkably, this small structural difference is associated with an 80% decrease in uptake of FEC in PC-3 prostate cancer cells, whereas FMEC, which adds a methylene group to a nonradioactive methyl group, shows only a 50% decrease in tracer accumulation in PC-3 cells. Furthermore, whereas FCH and FMEC showed equivalent in vitro phosphorylation with choline, FEC was more poorly phosphorylated by CK (Table 1). Together, these data suggest that an ethyl-for-methyl substitution on choline tracers lowers their affinity for prostate cancer cells but not for CK. Fluorine-for-hydrogen substitution is well tolerated on the methyl group of FCH but is poorly tolerated on the ethyl group of FEC for uptake by PC-3 prostate cancer cells. The progressive decrease in phosphorylation rate as the size of the 18F radiolabel–containing side chain is increased from fluoromethyl to fluoropropyl suggests steric hindrance of CK-catalyzed phosphorylation for analogs having fluorine-containing substituents larger than the fluoromethyl group. Surprisingly, uptakes of FCH and FPC by PC-3 cells were nearly equivalent despite a large difference in affinity of these 2 tracers for CK-mediated phosphorylation (Table 1). It is possible that the uptakes of FCH and FPC by cultured cancer cells are rate limited at the transport step (33) and the affinity of FCH and FPC for the choline transporter is similar. Accordingly, studies with a broad range of N-alkyl substitutions are needed to further clarify the structure–activity relationships for uptake of positron-labeled choline analogs by cancer cells. Although perfusion and transmembrane transport would presumably determine the rate of uptake of the radiolabeled choline analogs by tumors in vivo, the phosphorylation process is thought to be essential for metabolic retention of the choline-based tracers within cancer cells.
The preliminary imaging studies show excellent imaging feasibility of FCH in brain tumor, prostate cancer, and breast cancer. Clearly, further clinical studies on a larger number of subjects are needed to evaluate the clinical utility of FCH PET scans in these cancers. The longer half-life of 18F (110 min) is better suited for the demands of clinical PET than is 11C and may allow off-site production and distribution of the radiotracer. The very low uptake of FCH by normal cerebral cortex is a major advantage that FCH appears to share with [11C]choline (5) relative to FDG for imaging brain tumors. In prostate cancer, the visualization of cancer in the prostate gland and neighboring tissues early after injection without confounding radioactivity in the urinary bladder is an advantage that FCH appears to share with CH, although later urinary radioactivity may be higher with FCH relative to [11C]choline (11). The different pattern of uptake of FDG and FCH in the right anterior pelvic tumor of the breast cancer patient (patient 3) was an interesting finding that may point to differences in the physiology of the 2 tracers. A plausible explanation of the more peripheral deposition of FCH in the tumor relative to FDG is that FCH uptake is more dependent on flow than is FDG uptake and the inner core of this tumor was poorly perfused. FDG has a much slower clearance from the circulation, allowing more time for the tracer to accumulate in poorly perfused tissues. In contrast, the residence time of FCH is very short (<2 min) in the circulation. Perfusion and blood-to-tissue choline transport likely play a major role in the distribution of FCH to tissues, although as noted, phosphorylation and subsequent metabolic steps are presumably involved in retention of the early biodistribution pattern.
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CONCLUSION |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONCONCLUSIONREFERENCES |
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ACKNOWLEDGMENTS |
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FOOTNOTES |
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For correspondence or reprints contact: Timothy R. DeGrado, PhD, Department of Radiology, Duke University Medical Center, Box 3949, Durham, NC 27710.
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REFERENCES |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONCONCLUSIONREFERENCES |
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A. Dimitrakopoulou-Strauss and L. G. Strauss PET Imagin |
