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Synthesis, Biochemistry, and Prostate Cancer Imaging

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Synthesis, Biochemistry, and Prostate Cancer Imaging Development of 18F-Fluoroethylcholine for Cancer Imaging with PET: Synthesis, Biochemistry, and Prostate Cancer Imaging Toshihiko Hara, MD, PhD1; Noboru Kosaka, MD1; and Hiroichi Kishi, MD, PhD2 1Department of Radiology, International Medical Center of Japan, Tokyo, Japan; and 2Department of Urology, International Medical Center of Japan, Tokyo, Japan phoryl-18F-FECh, seemed to be involved in the uptake mecha- 18 The effectiveness of 11C-choline PET in detecting various can- nism of F-FECh in tumors. cers, including prostate cancer, is well established. This study Key Words: 18F; choline; PET; prostate cancer was aimed at developing an 18F-substituted choline analog, J Nucl Med 2002; 43:187–199 18F-fluoroethylcholine (FECh), as a tracer of cancer detection. Methods: No-carrier-added 18F-FECh was synthesized by 2-step reactions: First, tetrabutylammonium (TBA) 18F-fluoride was reacted with 1,2-bis(tosyloxy)ethane to yield 2-18F-fluoro- ethyl tosylate; and second, 2-18F-fluoroethyl tosylate was re- In most cancers a high content of phosphorylcholine has acted with N,N-dimethylethanolamine to yield 18F-FECh, which been revealed by 31P nuclear magnetic resonance (NMR) was then purified by chromatography. An automated apparatus studies, whereas in the corresponding normal tissues phos- was constructed for preparation of the 18F-FECh injection solu- phorylcholine is present at low levels, occasionally below tion. In vitro experiments were performed to examine the uptake detection (1,2). Phosphorylcholine, a product of the choline of 18F-FECh in Ehrlich ascites tumor cells, and the metabolites kinase reaction, is the first intermediate in the stepwise were analyzed by solvent extraction followed by various kinds of ϩ chromatography. Clinical studies of 18F-FECh PET were per- incorporation of choline, (CH3)3N CH2CH2OH, into phos- formed on patients with untreated primary prostate cancer as pholipids by the Kennedy pathway. Katz-Brull and Degani follows: A dynamic 18F-FECh PET study was performed on 1 (3) investigated choline transport in human breast cancer patient and static PET studies were performed on 16 patients, cells in vitro by 31P, 13C, and 2H NMR and found that and the data were compared with those of 11C-choline PET on choline was incorporated into the tumor cells by a carrier- the same patients. Results: 18F-FECh was prepared in high mediated mechanism and then it was converted into phos- yield and purity. The performance of the automated apparatus 18 phorylcholine within 1 h. Haeffner (4) investigated choline was excellent. The in vitro experiment revealed that F-FECh 3 was incorporated into tumor cells by active transport, then transport in Ehrlich ascites tumor cells using H-choline and 14 phosphorylated (yielding phosphoryl-18F-FECh) in the cells, and C-choline. When choline was incubated with tumor cells finally integrated into phospholipids. The clinical PET studies at a low concentration, it was incorporated into the cells by showed marked uptake of 18F-FECh in prostate cancer. A dy- an active-transport mechanism, then it was converted into namic PET study on 1 patient revealed that the blood level of phosphorylcholine also within 1 h, and finally it was inte- 18F-FECh decreased rapidly (in 1 min), the prostate cancer level grated into phosphatidylcholine. became almost maximal in a short period (1.5 min) and it re- We previously developed 11C-choline as a PET tracer for mained constant for a long time (60 min), and the urinary radio- cancer detection and have succeeded in visualizing brain activity became prominent after a short time lag (5 min). Static PET studies conducted under bladder irrigation showed no tumor (5), lung cancer (6), esophageal cancer (7), colon difference between 18F-FECh uptake and 11C-choline uptake in cancer (8), bladder cancer (8), prostate cancer (9), and many prostate cancer. However, 18F-FECh gave a slightly higher spa- other cancers (8). Motivated by this success, we attempted tial resolution of the image, which was attributed to the shorter to develop an 18F-labeled choline analog as a PET tracer, positron range of 18F. Conclusion: The synthesis of 18F-FECh with an idea that 18F labeling would be superior to 11C was easy and reliable. 18F-FECh PET was very effective in labeling because of the longer half-life and the shorter detecting prostate cancer in patients. The chemical trap, con- positron range of 18F. We thought that 18F-fluoroethylcho- sisting of active transport of 18F-FECh and formation of phos- line (FECh) would be appropriate for this purpose. The following evidence supports our idea: Deves and Krupka Received Mar. 1, 2001; revision accepted Jun. 14, 2001. (10) studied the binding affinity of the choline transport For correspondence or reprints contact: Toshihiko Hara, MD, PhD, Depart- system for synthetic choline analogs, using red blood cells, ment of Radiology, International Medical Center of Japan, 1-21-1 Toyama, Shinjuku-ku, Tokyo 162, Japan. and found that 2 methyl groups were essential, but the third E-mail: [email protected] methyl group was replaceable with a longer alkyl group. 18F-FLUOROETHYLCHOLINE FOR PROSTATE CANCER IMAGING • Hara et al. 187 Clary et al. (11) studied the substrate specificity of choline dried over MgSO4 and evaporated in vacuo to give an oil. Thin- kinase for synthetic choline analogs, using yeast choline layer chromatography (TLC) (silica gel; n-hexane:ethyl acetate, kinase, and found that the 2 methyl groups and the hydroxyl- 3:1) of the oil showed 3 reaction products: vinyl tosylate (Rf, 0.57), ethyl side chain were essential, but the third methyl group 2-fluoroethyl tosylate (Rf, 0.36), and 1,2-bis(tosyloxy)ethane (Rf, was replaceable with a longer alkyl group. We had already 0.21). The product was purified by column chromatography (silica synthesized 18F-FECh and studied its biodistribution in nor- gel; n-hexane:ethyl acetate, 5:1) to give 2-fluoroethyl tosylate as a colorless oil (4.4 g, 67%). 1H NMR (CDCl ): ␦ 2.46 (s, 3H), 4.28 mal and tumor-bearing rabbits; our results are reported in a 3 (dt, J ϭ 27.3, 4.0 Hz, 2H), 4.56 (dt, J ϭ 47.0, 4.0 Hz, 2H), 7.37 (d, preliminary form (12). In this article, we report the details of J ϭ 7.9 Hz, 2H), 7.82 (d, J ϭ 7.9 Hz, 2H). MS: m/z 218, 172, 155, the synthesis, biochemistry, and clinical application of this and 91. High-resolution MS: calculated for C9H11FSO3, 218.041; compound. observed, 218.042. The product was analyzed by high-perfor- mance liquid chromatography (HPLC): Column, ODS-silica gel MATERIALS AND METHODS (ODS-A; YMC), 250 ϫ 10 mm; solvent, 50 mmol/L phosphoric ϩ Synthesis of 18F-FECh acid 1 mmol/L 2-naphthalenesulfonic acid; flow rate, 5 mL/min; We first synthesized nonradioactive FECh (fluoroethanol detector, refractometer. The retention time of the product was 3.9 method) and then used it as standard for the synthesis of radioac- min. tive (no-carrier-added) 18F-FECh (tetrabutylammonium [TBA] FECh Tosylate (Fluoroethanol Method). 2-Fluoroethyl tosylate method) (Fig. 1). (996 mg, 4.56 mmol) was dissolved in N,N-dimethylethanolamine Reagents were purchased from Sigma-Aldrich Japan (Tokyo, (407 mg, 4.56 mmol) and, under argon, heated at 100°C for 10 Japan), Merck Japan (Tokyo, Japan), Wako (Osaka, Japan), Tokyo min. The resultant syrup was dissolved in methyl acetate:methanol Kasei (Tokyo, Japan), YMC Co. (Kyoto, Japan), Nihon Waters (10:1), and the solvent was removed by evaporation to give the (Tokyo, Japan), or Dionex Japan (Tokyo, Japan). 1H NMR (300 product as colorless rhomboid crystals. After recrystallization from 1 MHz) was measured with an NMR spectrometer (JNM-AL300 FT; the same solvent, mp 63.9°C–64.5°C (1.43 g, 100%). H NMR ␦ JEOL, Tokyo, Japan). The mass spectrum (MS) was measured (CD3OD): 2.37 (s, 3H), 3.23 (s, 6H), 3.54–3.61 (m, 2H), 3.76– with a mass spectrometer (GCMS-QP5050; Shimadzu, Kyoto, 4.04 (m, 4H), 4.90 (bd, J ϭ 48.0 Hz, 2H), 7.23 (d, J ϭ 8.4 Hz, 2H), Japan). High-resolution mass spectrometry was performed by 7.71 (d, J ϭ 8.4 Hz, 2H). IR (KBr): 3,375, 2,976, 1,478, 1,213, Ϫ Daikin Industries (Tsukuba, Japan). The infrared (IR) spectrum 1,195, 1,124, 1,035, 1,012, and 684 cm 1. was measured with an IR spectrometer (FTIR-8300; Shimadzu). FECh Chloride (Fluoroethanol Method). FECh tosylate (50 mg, The quantitative analysis of FECh was performed by ion chroma- 0.16 mmol) was dissolved in methanol (20 mL) and passed Ϫ tography (Dionex DX-120; Dionex Japan). 18F-Fluoride anion was through an anion-exchange resin, Amberlite IRA-900 (Cl 1) produced by proton irradiation of 18O-water using a cyclotron (Sigma, St. Louis, MO) (3 g). Removal of methanol gave FECh (Baby Cyclotron 2010N; Japan Steel Works, Tokyo, Japan). chloride as colorless needle crystals (28 mg, 100%). 1H NMR 2-Fluoroethyl Tosylate (Fluoroethanol Method). At 0°C while (CD3OD): ␦ 3.27 (s, 6H), 3.58–3.65 (m, 2H), 3.82–4.07 (m, 4H), stirring in an argon atmosphere, 2-fluoroethanol (1.92 g, 30 mmol) 4.95 (bd, J ϭ 50.0 Hz, 2H). IR (KBr): 3,383, 3,020, 1,475, 1,082, and tosyl chloride (6.87 g, 36 mmol) were dissolved in dichlo- 957, 931, and 689 cmϪ1. romethane (30 mL), and pyridine (10 mL) and 4-dimethylamino- FECh Hydroxide (Fluoroethanol Method). FECh tosylate (40 pyridine (100 mg) were added. After remaining at room temper- mg, 0.13 mmol) was dissolved in water (30 mL) and passed ature for 3 d, the mixture was diluted with dichloromethane (100 through an anion-exchange resin, Amberlite IRA-900 (OHϪ1)(2 mL) and then washed with 5% HCl (3 times) and brine.
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