Synthesis of [18F]2-deoxy-2-fluoro-d-glucose and [18F]3-deoxy-3-fluoro-d-glucose with [18F]fluoride from a water target

A combined study of the labelling methods of two important glucose-derivatives i.e. [¹⁸F]2-deoxy-2-fluoro-d-glucose ([¹⁸F]2-FDG) and [¹⁸F]3-deoxy-3-fluoro-d-glucose ([¹⁸F]3-FDG) is described. Using [¹⁸F]fluoride as reacting agent produced in a water target via the ¹⁸O(p, n)¹⁸F and ¹⁶O(³He, p)¹⁸F reaction, respectively, nucleophilic aliphatic substitution was performed at the corresponding precursors i.e. methyl-4-,6-O-benzylidene-2,3-O-cyclic-sulfato-β-d-mannopyranoside and 1,2:5,6-di-O-isopropylidene-3-O-trifluoromethanesulfonyl-α-d-allofuranose. After hydrolysis of the corresponding intermediate [¹⁸F]2-FDG and [¹⁸F]3-FDG were obtained as injectable solutions with yields of 22 and 40% (decay corrected), respectively.     

Contamination of 2-deoxy-2-[18F]fluoro-d-mannose in the 2-deoxy-2-[18F]fluoro-d-glucose preparations synthesized from [18F]acetyl hypofluorite and [18F]F2

The presence of 2-deoxy-2-[¹⁸F]fluoro-d-mannose ([¹⁸F]FDM) in 2-deoxy-2-[¹⁸F]fluoro-d-glucose ([¹⁸F]FDG) prepared by the reaction of 3,4,6-tri-O-acetyl-d-glucal (TAG) with [¹⁸F]acetyl hypofluorite ([¹⁸F]CH₃COOF) or [¹⁸F]F₂ was quantified by radio HPLC analysis of reacetylated [¹⁸F]FDG. The solvent effects on the stereoselectivity of the reaction of TAG with [¹⁸F]CH₃COOF were examined in six kinds of solvent.Reaction of TAG with [¹⁸F]CH₃COOF in Freon-11 results in the least contamination of [¹⁸F]FDM (4–5%). The presence of [¹⁸F]FDM in the [¹⁸F]FDG prepared from TAG with [¹⁸F]F₂ was also indicated, but by careful chromatographic separation of hexopyranosyl difluorides the amount was reduced to nearly that resulting from the [¹⁸F]CH₃COOF method.     

Synthesis of [18F]2-deoxy-2-fluoro-D-glucose from highly reactive [18F]tetraethylammonium fluoride prepared by hydrolysis of [18F]fluorotrimethylsilane

18F-Labeled fluorotrimethylsilane was prepared by nucleophilic substitution of chlorotrimethylsilane with reactor produced [18F]fluoride. Hydrolysis of fluorotrimethylsilane by aqueous tetraethylammonium hydroxide followed by removal of water with a mechanical pump gave a powerful source of no carrier added nucleophilic 18F. Reaction of this purified 18F preparation with 4,6-benzylidene-1-beta-O-methyl D-mannopyranoside-2.3-cyclic sulfate was complete in 2 min at 80 degrees C and gave two labeled products with similar retention times on reverse phase HPLC. Allowing for decay and handling losses during deprotection, the maximum yield of [18F]2-deoxy-2-fluoro-D-glucose from no-carrier added tetraethylammonium fluoride was 50%. Incorporation of 18F into organic products was 30% complete in 10 min at room temperature. An identical time-course was observed for reaction of 3-O-triflyl-1,2-5,6-diisopropylidene-D-allofuranose, the starting material for 3-deoxy-3-fluoro-D-glucose. Reaction of tetraethylammonium fluoride with chlorotrimethylsilane was more rapid and much more tolerant of water than the fluorosugar reactions. Chlorotrimethylsilane can be used to recover unreacted 18F from reaction mixtures.     

Synthesis of 4-[18F]fluoroantipyrine and its biodistribution in mice

The synthesis of 4-[18F]fluoroantipyrine (1) and its biodistribution in mice are described. Compound 1 was synthesized either by direct fluorination of antipyrine with [18F]F2 or CH3CO2 18F, or by an isotopic exchange method. While direct fluorination of antipyrine with [18F]F2 gave compound 1 in about a 20% yield, the isotopic exchange method gave compound 1 in only a 1%-2% yield. The biodistributions of compound 1 and 4-[131I]iodoantipyrine (3) in mice indicated that both compounds reached apparent equilibrium concentration in the bloodstream at approximately 0.5 min postinjection and compound 1 was found in higher concentrations than the iodinated analog in the well-perfused tissues. The 18F activity in the mouse brain persisted for about 2 min. The ratio of activity in the brain to bone was approximately 2:1. After 10 min, the 18F activity in the brain decreased markedly while the 18F activity in bones rose sharply resulting in a brain to bone ratio of approximately 1:2. This would suggest that compound 1 defluorinated in vivo to give fluoride as one of the metabolites. The mean octanol/pH 7 buffer solution partition coefficients of 4-[18F]fluoroantipyrine and 4-[131I]iodoantipyrine were 5.18 +/- 0.10 and 11.34 +/- 0.28, respectively.     

Synthesis of 4-[18F]fluoroantipyrine and its biodistribution in mice

The synthesis of 4-[¹⁸F]fluoroantipyrine (1) and its biodistribution in mice are described. Compound 1 was synthesized either by direct fluorination of antipyrine with [¹⁸F]F₂ or CH₃CO₂ ¹⁸F, or by an isotopic exchange method. While direct fluorination of antipyrine with [¹⁸F]F₂ gave compound 1 in about a 20% yield, the isotopic exchange method gave compound 1 in only a 1%–2% yield. The biodistributions of compound 1 and 4-[¹³¹I]iodoantipyrine (3) in mice indicated that both compounds reached apparent equilibrium concentration in the bloodstream at approximately 0.5 min postinjection and compound 1 was found in higher concentrations than the iodinated analog in the well-perfused tissues. The ¹⁸F activity in the mouse brain persisted for about 2 min. The ratio of activity in the brain to bone was approximately 2:1. After 10 min, the ¹⁸F activity in the brain decreased markedly while the ¹⁸F activity in bones rose sharply resulting in a brain to bone ratio of approximately 1:2. This would suggest that compound 1 defluorinated in vivo to give fluoride as one of the metabolites.The mean octanol/pH 7 buffer solution partition coefficients of 4-[¹⁸F]fluoroantipyrine and 4-[¹³¹I]iodoantipyrine were 5.18±0.10 and 11.34±0.28, respectively.     

Synthesis and biodistribution of [18F]-5-fluorocytosine

[18F]-5-fluorocytosine was prepared by reaction of [18F]-acetylhypofluorite with cytosine in acetic acid and was isolated in an overall radiochemical yield of 20%. Tissue distribution studies in sarcoma-bearing rats indicated in vivo stability, limited tissue uptake and rapid urinary excretion.     

Positron labeled antioxidants: Synthesis and tissue biodistribution of 6-deoxy-6-[18F]fluoro-l-ascorbic acid

A one-pot synthesis of 6-deoxy-6-[¹⁸F]fluoro-l-ascorbic acid (¹⁸F-DFA) has been developed via nucleophilic displacement of a cyclic sulfate with no-carrier-added [¹⁸F]fluoride ion. Isolated radiochemical yields of around 15% were obtained with radiochemical purity of over 99% after overall synthesis time of 90 min. Tissue distribution studies with ¹⁸F-DFA in rats showed high uptake of radioactivity in the adrenals, kidneys, liver and small intestine—organs known to have high concentrations of l-ascorbic acid. The slow and low uptake of radioactivity in the brain was observed between 10 and 120 min after i.v. injection. In vivo behavior of ¹⁸F-DFA in mice bearing 3-methylcholanthrene-induced fibrosarcoma demonstrated its ability to accumulate in the tumor.     

Synthesis and purification of 2-deoxy-2-[18F]fluoro-d-glucose and 2-deoxy-2-[18F]fluoro-d-mannose: characterization of products by 1H- and 19F-NMR spectroscopy

A procedure has been developed that allows the separation of 2-deoxy-2-[¹⁸F]fluoro-d-glucose from 2-deoxy-2-[¹⁸F]fluoro-d-mannose employing selectively optimized ion-moderated partition chromatography. Both compounds can be obtained with a >98% chemical and radiochemical purity in about one half-life of ¹⁸F. Both the α- and β-anomers of both sugars were completely characterized by high-resolution ¹H- and ¹⁹F-NMR spectroscopy. Various convenient preparation methods for 2-deoxy-2-[¹⁸F]fluoro-d-glucose were compared.     

Robotic production of 2-deoxy-2[18F]fluoro-d-glucose: A routine method of synthesis using tetrabutylammonium [18F]fluoride

Using existing robotic hardware and software programs developed for the synthesis of several positron-emitting radiopharmaceuticals for PET imaging [Brodack et al. (1988) Appl. Radiat. Isot.39, 689], the additional automated synthesis of 2-deoxy-2-[¹⁸F]fluoro-d-glucose (2-[¹⁸F]FDG) has been incorporated into our Zymate Laboratory Automation System. The robotic synthesis of 2-[¹⁸F]FDG took less than one week to implement, including the organization of software subroutines and construction of an additional heating station. The end of synthesis yield (12–17%) and radiochemical purity (96–99%) for the robotic preparation of 2-[¹⁸F]FDG is similar to that of the manual synthesis. This automated method uses anhydrous tetrabutylammonium [¹⁸F]fluoride as the reactive fluoride source in the labeling step. The procedure is a modification of the synthesis reported by Hamacher et al. [Hamacher et al. (1986) J. Nucl. Med.27, 235].     

2-[18F]Fluoroethanol and 3-[18F]fluoropropanol: facile preparation,biodistribution in mice,and their application as nucleophiles in the synthesis of [18F]fluoroalkyl aryl ester and ether PET tracers

Introduction2-[¹⁸F]Fluoroethoxy and 3-[¹⁸F]fluoropropoxy groups are common moieties in the structures of radiotracers used with positron emission tomography. The objectives of this study were (1) to develop an efficient one-step method for the preparation of 2-[¹⁸F]fluoroethanol (2-[¹⁸F]FEtOH) and 3-[¹⁸F]fluoropropanol (3-[¹⁸F]FPrOH); (2) to demonstrate the feasibility of using 2-[¹⁸F]FEtOH as a nucleophile for the synthesis of 2-[¹⁸F]fluoroethyl aryl esters and ethers; and (3) to determine the biodistribution profiles of 2-[¹⁸F]FEtOH and 3-[¹⁸F]FPrOH in mice.Methods2-[¹⁸F]FEtOH and 3-[¹⁸F]FPrOH were prepared by reacting n-Bu₄N[¹⁸F]F with ethylene carbonate and 1,3-dioxan-2-one, respectively, in diethylene glycol at 165 °C and purified by distillation. 2-[¹⁸F]fluoroethyl 4-fluorobenzoate and 1-(2-[¹⁸F]fluoroethoxy)-4-nitrobenzene were prepared by coupling 2-[¹⁸F]FEtOH with 4-fluorobenzoyl chloride and 1-fluoro-4-nitrobenzene, respectively. Biodistribution and PET/CT imaging studies of 2-[¹⁸F]FEtOH and 3-[¹⁸F]FPrOH were performed in normal female Balb/C mice.ResultsThe preparation of 2-[¹⁸F]FEtOH and 3-[¹⁸F]FPrOH took 60 min, and their decay-corrected yields were 88.6 ± 2.0% (n = 9) and 65.6 ± 10.2% (n = 5), respectively. The decay-corrected yields for the preparation of 2-[¹⁸F]fluoroethyl 4-fluorobenzoate and 1-(2-[¹⁸F]fluoroethoxy)-4-nitrobenzene were 36.1 ± 5.4% (n = 3) and 27.7 ± 10.7% (n = 3), respectively. Imaging/biodistribution studies in mice using 2-[¹⁸F]FEtOH showed high initial radioactivity accumulation in all major organs followed by very slow clearance. On the contrary, by using 3-[¹⁸F]FPrOH, radioactivity accumulated in all major organs was cleared rapidly, but massive in vivo defluorination (31.3 ± 9.57%ID/g in bone at 1 h post-injection) was observed.ConclusionsUsing 2-[¹⁸F]FEtOH/3-[¹⁸F]FPrOH as a nucleophile is a competitive new strategy for the synthesis of 2-[¹⁸F]fluoroethyl/3-[¹⁸F]fluoropropyl aryl esters and ethers. Our biodistribution data emphasize the importance of in vivo stability of PET tracers containing a 2-[¹⁸F]fluoroethyl or 3-[¹⁸F]fluoropropyl group due to high background and high bone uptake resulting from 2-[¹⁸F]FEtOH and 3-[¹⁸F]FPrOH, respectively. This is especially important for their aryl ester derivatives which are prone to in vivo hydrolysis.     

Radiofluorination with reactor-produced Cesium [18F]fluoride: No-carrier-added [18F]2-fluoronicotine and [18F]6-fluoronicotine

We have synthesised no-carrier-added [¹⁸F]2-fluoronicotine by the halogen-exchange reaction of reactor-produced Cs¹⁸F upon 2-bromonicotine in refluxing DMSO. No special drying of the Cs¹⁸F was required. [¹⁸F]2-Fluoronicotine was isolated by reversed-phase HPLC and production of 220 MBq (6 mCi) ready for injection represented a decay-corrected radiochemical yield of 23% and required 3.5 h from end-of-bombardment. Similarly, [¹⁸F]6-fluoronicotine was prepared from 6-bromonicotine in amounts of 80 MBq (2.2 mCi) or 8% yield. These quantities are sufficient for studies in humans.     

2-[18F]fluoroputrescine: Preparation,biodistribution, and mechanism of defluorination

A new radiolabeled analog of putrescine, ¹⁸F labeled 2-fluoroputrescine, has been prepared as a potential in vivo imaging agent for prostate and prostate derived tumors. The radiosynthesis yielded 1.5–4.5 mCi amounts of the ¹⁸F labeled putrescine analog (1–3% yields at end-of-synthesis), with specific activities ranging from 0.85–4.3 Ci/mmol, in a synthesis time of 2 h. The in vivo biodistribution in mature male rats showed considerable uptake by the bone, indicating defluorination of the compound. In animals pretreated with aminoguanidine, an inhibitor of diamine oxidase, the enzyme important in the metabolism of putrescine, defluorination was markedly reduced, but uptake by the prostate did not improve. These results suggest the need for development of a ¹⁸F labeled analog of putrescine which does not defluorinate in vivo, and which has biological properties similar to putrescine.     

Synthesis and tumour-localizing properties of [18F]-5-fluorocytosine-arabinoside and [18F]-5-fluorocyclocytidine

[18F]-5-fluorocytosine-arabinoside (2) and [18F]-5-fluorocyclocytidine (4) were prepared by reaction of [18F]-acetylhypofluorite with cytosine-arabinoside (1) or cyclocytidine (3) in acetic acid and were isolated in an overall radiochemical yield of 20% and 9%, respectively. The biodistribution of both radiopharmaceuticals was determined in melanoma bearing Syrian golden hamsters. It was found that 2 is a good tumour-localizing agent for pigmented and non-pigmented Greene melanoma.     

Synthesis and biodistribution of 2-[123I]iodomelatonin in normal mice.

Melatonin demands that this hormone and its receptors be well understood. With this aim in mind, synthetic melatonin was radioiodinated with no-carrier-added (n.c.a.) sodium iodide-123 using in situ generated peracetic acid as oxidizing agent for electrophilic iodination at room temperature. The radiochemical yield was typically greater than 80% after 20 min reaction time especially when relatively small amounts of activities were used (相似文献   

Synthesis and tumour-localizing properties of [18F]-5-fluorocytosine-arabinoside and [18F]-5-fluorocyclocytidine

[¹⁸F]-5-fluorocytosine-arabinoside (2) and [¹⁸F]-5-fluorocyclocytidine (4) were prepared by reaction of [¹⁸F]-acetylhypofluorite with cytosine-arabinoside (1) or cyclocytidine (3) in acetic acid and were isolated in an overall radiochemical yield of 20% and 9%, respectively. The biodistribution of both radiopharmaceuticals was determined in melanoma bearing Syrian golden hamsters. It was found that 2 is a good tumour-localizing agent for pigmented and non-pigmented Greene melanoma.