Development of [18F]FRP-170 injection for imaging hypoxia by PET

A novel [18F]FRP-170 injection for imaging hypoxia by PET was developed for clinical use. The preparation was based on the simple on-column basic-hydrolysis and the whole procedure was automated by detecting He flow change for transferring and evaporating liquids. [18F]FRP-170 was prepared in around 15-20% decay-corrected radiochemical yield within 60 min and stable in saline for more than 6 hr. Radiochemical purity was over 99% and specific activity at EOS was 40-60 GBq/micromol. The radiation-absorbed dose to the whole body was estimated to be 1.0 mSv/185 MBq. The [18F]FRP-170 injection proved to be suitable for clinical use without acute toxicity or mutagenicity.     

18F]fluoromethyl triflate, a novel and reactive [18F]fluoromethylating agent: preparation and application to the on-column preparation of [18F]fluorocholine.

The production and use of [18F]fluoromethyl triflate ([18F]CH2FOTf), a more reactive [18F]fluoromethylating agent than [18F]fluoromethyl bromide ([18F]CH2BrF), is described. [18F]CH2FOTf was prepared from [18F]CH2BrF. The latter was synthesized by nucleophilic substitution of CH2Br2 with no-carrier-added [18F]fluoride and purified by four Sep-Pak Plus silica cartridges connected in series. It was then quantitatively converted on-line to [18F]CH2FOTf by passing through a heated AgOTf column. Decay-corrected radiochemical yields of [18F]CH2FOTf based on [18F]fluoride were 47 +/- 8% (n = 20). Both [18F]CH2BrF and [18F]CH2FOTf were applied to solid-supported [18F]fluoromethylation of N,N-dimethylaminoethanol on a Sep-Pak Plus C18 cartridge to produce the 18F-labeled choline analogue, (beta-hydroxyethyl)dimethyl-[18F]fluoromethylammonium ([18F]fluorocholine). Depending on flow rate and amount of precursor used, decay corrected radiochemical yields of [18F]fluorocholine from [18F]CH2BrF ranged from 6% to 63%, while [18F]CH2FOTf afforded yields of more than 80%. Thus, by using the latter reagent and a subsequent purification on a Sep-Pak Accell CM cartridge, [18F]fluorocholine was produced from [18F]fluoride in overall radiochemical yields of 40% (decay corrected) in less than 30 min.     

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.     

Automated synthesis of 16alpha-[18F]fluoroestradiol-3,17beta-disulphamate.

After 16alpha-[15F]fluoroestradiol ([18F]FES) has been successfully prepared in an automated module, the synthesis of 16alpha-[18F]fluoroestradiol-3,17beta-disulphamate ([18F]FESDS) is described as a module-assisted one-pot procedure which can provide 10GBq [18F]FESDS with a radiochemical purity better than 99%. The procedure is reliable and reproducible and requires a time of about 90 min. Because of its high sulphatase-inhibitory effect [15F]FESDS is thought to be a new PET tracer to image sites of high sulphatase activity.     

Automated synthesis of [18F]gefitinib on a modular system

In recent years, [(18)F]gefitinib PET has successfully been employed for a number of applications ranging from oncology to in vivo studies of drug transporter proteins. We here report a reliable, automated procedure for routine synthesis of this radiotracer on an Eckert and Ziegler modular system. The 3-step radiosynthesis followed by preparative HPLC-purification provided [(18)F]gefitinib in 17.2±3.3% (n=22) overall decay-corrected radiochemical yield with radiochemical purity >99% in a total synthesis time of about 2.5h.     

Pharmacokinetics of [18F]FETNIM: a potential marker for PET.

18F-labeled fluoroerythronitroimidazole (FETNIM) has been suggested as a marker of tumor hypoxia for use with PET. Our goal was to evaluate the pharmacokinetic properties of [18F]FETNIM in rats and analyze metabolites in human, dog, and rat plasma and urine. Metabolites in liver and tumor homogenates from tumor-bearing rats, as well as the biodistribution of the tracer, were also studied. METHODS: Radio-thin-layer chromatography and digital autoradiography were used to distinguish metabolites from the parent drug in urine and plasma from 8 patients, 3 dogs, and 18 rats, as well as in liver and tumor homogenates from Sprague-Dawley rats bearing 7,12-dimethylbenzanthracene-induced rat mammary carcinoma. Biodistribution of [18F]FETNIM was also studied in rats at 15, 30, 60, 120, and 240 min after tracer injection. RESULTS: Most of the radioactivity in plasma and urine was the unchanged tracer, whereas rat liver homogenates contained almost only metabolites of [18F]FETNIM. None of the species studied showed binding of tracer to plasma proteins. A large variation-3%-70%-in the radioactivity represented by unchanged [18F]FETNIM was found in rat tumor. A negative correlation was found between the percentage of radioactivity represented by unchanged [18F]FETNIM in tumor tissue and tumor uptake (percentage injected dose per gram of tissue) at later times. The highest radioactivity was seen in urine and kidney; the lowest uptake was in fat, cerebellum, and bone matrix. In contrast to matrix, bone marrow had high uptake of 18F. The tumor-to-blood ratio reached a maximum of 1.80 +/- 0.64 at 2 h. CONCLUSION: We conclude that [18F]FETNIM shows low peripheral metabolism, little defluorination, and possible metabolic trapping in hypoxic tumor tissue. These suggest a potential use for this tracer in PET studies on hypoxia of cancer patients.     

No-carrier-added regioselective preparation of 6-[18F]fluoro-L-dopa

This paper describes the preparation of 6-[18F]fluoro-L-dopa by a no-carrier-added method based on the nucleophilic displacement of nitro groups of two commercially available substrates, 3,4-dimethoxy-2-nitrobenzaldehyde (nitroveratraldehyde) and 6-nitropiperonal. Fluorination was conducted in DMSO with fluorine-18 (18F) in the presence of the aminopolyether Kryptofix 222 and potassium carbonate. The condensation of the fluorinated aldehydes with phenyloxazolone and the subsequent hydrolysis with HI/P yield, after purification by HPLC, only the 6-(D, L) isomers. The racemic mixture (50/50) was resolved on an analytical scale chiral column. The method, which requires 100 min (EOB) to complete, produces 6-[18F]fluoro-L-dopa with a decay-corrected radiochemical yield of 10%, an enantiomeric purity greater than 99%, and a specific activity of 1.2 Ci/mumole.     

A complete remote-control system for reliable preparation of [18F]altanserin.

A complete remote control system was constructed for production of the PET 5-HT2A ligand [18F]altanserin by nitro-for-fluoro exchange. Comparing with published methods, the key features include (1) conducting azeotropic distillation and nucleophilic displacement in an open vessel heated by a commercial microwave oven; (2) purifying the product by a single HPLC procedure and (3) removing HPLC solvent by solid phase extraction. The preparation took 114 min with 23% yield and high quality.     

Recovery of [18F]fluoride from [18O]water in an electrochemical cell

The recovery of [¹⁸F]fluoride from [¹⁸O]water using an electric field to deposit and remove the fluoride is described. An electrolytic cell was constructed to study [¹⁸F]fluoride recovery as a function of voltage, voltage gradient, and time using vitreous carbon and platinum electrodes. The fluoride ion is both deposited onto and removed from the carbon electrode most efficiently at voltages more than 10 V. Typically 95% of the ¹⁸F activity from the target could be deposited onto the carbon electrode. Seventy percent of the activity deposited could then be released from the carbon electrode after excitation of the cell with an electric field of an opposite polarity and equal magnitude to the deposition field. These efficiencies were obtained after excitation of the cell for 5 min for both the deposition and the release of [¹⁸F]fluoride.The reactivity of [¹⁸F]fluoride reclaimed from the electrolytic cell was probed using the syntheses of 2-deoxy-2-[¹⁸F]fluoro-d-glucose and para[¹⁸F]fluoronitrobenzene as test systems.     

Comparison of [18F]FDOPA, [18F]FMT and [18F]FECNT for imaging dopaminergic neurotransmission in mice

INTRODUCTION: The clinically established positron emission tomography (PET) tracers 6-[(18)F]-fluoro-l-DOPA ([(18)F]FDOPA), 6-[(18)F]-fluoro-l-m-tyrosine ([(18)F]FMT) and 2beta-carbomethoxy-3beta-(4-chlorophenyl)-8-(2-[(18)F]-fluoroethyl)-nortropane ([(18)F]FECNT) serve as markers of presynaptic integrity of dopaminergic nerve terminals in humans. This study describes our efforts to adopt the methodology of human Parkinson's disease (PD) PET studies to mice. METHODS: The PET imaging characteristics of [(18)F]FDOPA, [(18)F]FMT and [(18)F]FECNT were analyzed in healthy C57BL/6 mice using the dedicated small-animal PET tomograph quad-HIDAC. Furthermore, [(18)F]FECNT was tested in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) mouse model of PD. RESULTS: [(18)F]FDOPA and [(18)F]FMT failed to clearly visualize the mouse striatum, whereas PET experiments using [(18)F]FECNT proved that the employed methodology is capable of delineating the striatum in mice with exquisite resolution. Moreover, [(18)F]FECNT PET imaging of healthy and MPTP-lesioned mice demonstrated that the detection and quantification of striatal degeneration in lesioned mice can be accomplished. CONCLUSIONS: This study shows the feasibility of using [(18)F]FECNT PET to analyze noninvasively the striatal degeneration in the MPTP mouse model of PD. This methodology can be therefore considered as a viable complement to established in vivo microdialysis and postmortem techniques.     

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.     

Automated synthesis of 18F analogue of paclitaxel (PAC): [18F]Paclitaxel (FPAC).

A positron-emitting paclitaxel (PAC) derivative could allow in vivo measurement of multidrug resistance in tumors and, therefore, predict a potential chemotherapeutic benefit to patients. [18F]Paclitaxel was produced using a 2-reaction vessel automated synthesizer followed by HPLC purification. Optimized reaction conditions resulted in radiochemical yields of 21.2+/-9.6% at end of bombardment, radiochemical purity >99%, and specific activity of 159+/-43 G Bq/micromol. [18F]Paclitaxel activities of 1.33+/-0.729 G Bq (n=7) were obtained in sterile, pyrogen-free solution for IV administration.     

Synthesis of 2'-deoxy-2'-[18F]fluoro-beta-D-arabinofuranosyl nucleosides, [18F]FAU, [18F]FMAU, [18F]FBAU and [18F]FIAU,as potential PET agents for imaging cellular proliferation. Synthesis of [18F]labelled FAU,FMAU, FBAU,FIAU

An efficient and reliable synthesis of 2'-deoxy-2'-[(18)F]fluoro-beta-D-arabinofuranosyl nucleosides is presented. Overall decay-corrected radiochemical yields of 35-45% of 4 analogs, FAU, FMAU, FBAU and FIAU are routinely obtained in >98% radiochemical purity and with specific activities of greater than 3 Ci/micromol (110 MBq/micromol) in a synthesis time of approximately 3 hours. When approximately 220 mCi (8.15 GBq) of starting [(18)F]fluoride is used, 25 -30 mCi (0.93 -1.11 GBq) of product (enough to image two patients sequentially) is typically obtained.     

Automated synthesis and purification of [18F]bromofluoromethane at high specific radioactivity

[¹⁸F]Bromofluoromethane was synthesised from dibromomethane by substitution of bromine with [¹⁸F]fluoride. The synthesis and separation of the [¹⁸F]bromofluoromethane were automated. [¹⁸F]Bromofluoromethane was used to convert a phenolic and a thiophenolic precursor into a labelled ether and thioether, respectively. The specific radioactivity of these labelled products was determined with both high-performance liquid chromatography (with UV-absorbance detection) and liquid chromatography (with mass spectrometric detection). The median for the specific radioactivity, corrected at the end of radionuclide production, was 934 GBq/μmol (range 40–9900 GBq/μmol; n=83).     

Carrier-added and no-carrier-added syntheses of [18F]spiroperidol and [18F]haloperidol

Syntheses of [18F]haloperidol and [18F]spiroperidol in both no-carrier-added and carrier-added forms have been accomplished. The no-carrier-added [18F]butyrophenone neuroleptics were prepared in low (less than 2%) yield by acid decomposition of aryl piperidine triazenes. Carrier-added 18F-neuroleptics were prepared in better (5-17%) yields by 18F-for-19F nucleophilic aromatic substitution. The preparation of all synthetic precursors, and procedures for radiolabeling are fully described.     

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.     

The synthesis of [18F]Xenon difluoride from [18F]fluoride gas

A convenient procedure for the rapid synthesis of ¹⁸F labelled XeF₂ was developed. Neon gas with 0.087 to 5% carrier fluorine was irradiated with 15 MeV deuterons to produce [¹⁸F]F₂ with a yield of 17 mCi/μAh, EOB. It was, in turn, reacted with excess of xenon in a high pressure nickel vessel at 390°C for 40 min. The isolated reaction product was XeF₂ exclusively. The production yield was 11 mCi/μAh at EOB and the specific activity was 450mCi/mmol. [¹⁸F]XeF₂ has been shown to be a versatile intermediate for the syntheses of ¹⁸F-labelled radiopharmaceuticals, for example, [¹⁸F]2-fluoro-2-deoxy-D-glucose and L-[¹⁸F]6-fluorodopa.