Synthesis and Evaluation of 18F-Labeled Choline Analogs as Oncologic PET Tracers

Synthesis and Evaluation of ¹⁸F-Labeled Choline Analogs as Oncologic PET Tracers

Timothy R. DeGrado, Steven W. Baldwin, Shuyan Wang, Matthew D. Orr, Ray P. Liao, Henry S. Friedman, Robert Reiman, David T. Price and R. Edward Coleman

Departments of Radiology, Chemistry, Surgery, Pediatrics, and Radiation Safety, Duke University Medical Center, Durham, North Carolina

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FIGURE 1. Chemical structures of positron-labeled choline analogs.

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FIGURE 2. Cation-exchange HPLC radiochromatograms of FCH (A), FEC (B), and FPC (C) final products. UV = ultraviolet.

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FIGURE 3. Normal phase, gradient-HPLC analysis of FCH and [¹⁴C]CH (A); P-FCH and [¹⁴C]phosphoryl-CH enzymatically synthesized using yeast CK according to method of Ishidate and Nakazawa (15) (B); and hydrophilic radiolabeled metabolites in cultured PC-3 prostate cancer cells after incubation with FCH and CH (C). Close correspondence of chromatograms B and C indicates extensive intracellular phosphorylation of FCH and CH in cancer cells.

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FIGURE 4. In vitro phosphorylation of FCH and CH by CK. Incubations were performed at room temperature with 25 mU/mL CK over choline concentrations of 0.001–10 mmol/L. Each data point represents results as mean ± SD of 3 samples. Similar inhibition of FCH and CH phosphorylation at higher choline concentrations is indicative of competitive inhibition of FCH phosphorylation by choline.

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FIGURE 5. (A) Attenuation-corrected FCH PET image (coronal projection, 2–4 min after injection) of pelvic region of patient 1 having biopsy-proven recurrent local prostate carcinoma. Slice thickness is 12.9 mm. In this early image, radioactivity had not yet arrived at urinary bladder, allowing excellent delineation of recurrent disease in prostate bed (arrow). (B) Time–activity curves for FCH in same patient as in A show very rapid clearance of radioactivity from ROI placed on iliac artery, rapid accumulation of tracer in local prostate bed, and arrival of radioactivity in urinary bladder at >4 min after injection. (C) Attenuation-corrected whole-body scan (coronal projections) shows several foci of high FCH uptake in mediastinum suggestive of prostate cancer in hilar and paraaortic lymph nodes. L = left.

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FIGURE 6. Patient with biopsy-confirmed recurrent anaplastic astrocytoma was imaged by T1-weighted Gd-diethylenetriaminepentaacetic acid–enhanced MRI, FCH PET (5–10 min after injection), and FDG PET (30–36 min after injection). MRI shows nodular enhancement posteriorly at postoperative cyst wall. FCH scan shows diffuse abnormal accumulation posteriorly and medially to cyst with focal areas of accumulation corresponding to nodular areas of enhancement on MRI scan. Note absence of normal cortex accumulation that is seen with FCH. FDG scan shows thin rim of abnormal accumulation that would support recurrent tumor, but abnormality is difficult to detect compared with FCH and MRI scans.

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FIGURE 7. Patient with metastatic breast cancer underwent FCH PET and FDG PET. Myocardial uptake is observed only with FDG, whereas more prominent uptake in salivary glands, liver, and kidneys is seen with FCH, which is consistent with normal uptake of choline by these tissues. Uptake of FDG and FCH is indicated in large metastases associated with sternum, right hilar and paratracheal lymph nodes, and right anterior pelvis. Volume of submanubrial metastasis was significantly larger on FCH PET scan. Smaller regions of focal uptake are observed on FCH PET scan in right chest wall and left lung (arrows) that are not seen on FDG PET scan. Uptake pattern of FDG was homogeneous across anterior pelvic metastasis, whereas FCH was taken up preferentially by periphery of this tumor.