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[en] Summary: The CGS 25966 derivative (R)-2-(N-Benzyl-4-(2-[18F]fluoroethoxy)phenyl-sulphonamido) -N-hydroxy-3-methylbutanamide [18F]9 represents a very potent radiolabelled matrix metalloproteinase inhibitor. For first human PET studies it is mandatory to have a fully automated radiosynthesis and a straightforward precursor synthesis available. The realisation of both requirements is reported herein. In particular, the corresponding precursor 8 was obtained in a reliable 7 step synthesis with an overall chemical yield of 2.3%. Furthermore, the target compound [18F]9 was prepared with a radiochemical yield of 14.8±3.9% (not corrected for decay).
[en] Histone deacetylase 6 (HDAC6) function and dysregulation have been implicated in the etiology of certain cancers and more recently in central nervous system (CNS) disorders including Rett syndrome, AlzheimerÐ“Ñ’Ð’Ð†Ð“Ñ’Ð²Ð‚Ñ™™s and ParkinsonÐ“Ñ’Ð’Ð†Ð“Ñ’Ð²Ð‚Ñ™™s diseases, and major depressive disorder. HDAC6-selective inhibitors have therapeutic potential, but in the CNS drug space the development of highly brain penetrant HDAC inhibitors has been a persistent challenge. Moreover, no tool exists to directly characterize HDAC6 and its related biology in the living human brain. Here, we report a highly brain penetrant HDAC6 inhibitor, Bavarostat, that exhibits excellent HDAC6 selectivity (>80-fold over all other Zn-containing HDAC paralogues), modulates tubulin acetylation selectively over histone acetylation, and has excellent brain penetrance. We further demonstrate that Bavarostat can be radiolabeled with 18F by deoxyfluorination through in situ formation of a ruthenium Ð“Ñ’Ð•Ñ‘Ð“Ñ’Ð²Ð‚Ñ™-complex of the corresponding phenol precursor: the only method currently suitable for synthesis of [18F]Bavarostat. In conclusion, by using [18F]Bavarostat in a series of rodent and nonhuman primate imaging experiments, we demonstrate its utility for mapping HDAC6 in the living brain, which sets the stage for first-in-human neurochemical imaging of this important target.
[en] Highlights: • Radiosynthesis of [18F]FBEM was performed in a TRACERlab FXN-Pro automated module. • [18F]FBEM was obtained from a 3-step reaction sequence in two separate reactors. • Total synthesis time from EOB to the [18F]FBEM was about 90 min. • The procedure can be applied in a routine preparation of [18F]FBEM. • Non-decay corrected radiochemical yield for [18F]FBEM was 7.5–18.8%. - Abstract: In the process of developing [18F]FBEM coupled target peptide, we have instituted a robust automated synthesis of [18F]FBEM, a sulfhydryl (-SH) site specific agent for radiolabeling of peptides and proteins. The radiosynthesis generated 1.67–3.89 GBq (45.1–105.1 mCi, 7.5–18.8% non-decay corrected yield) of [18F]FBEM from 22.2 GBq (600 mCi) of starting [18F]fluoride with molar activity of 31.8 ± 5.3 GBq/µmol (0.86 ± 0.14 mCi/nmol) (n = 3) at the end of synthesis. Radiochemical purity was greater than 98%, and total synthesis time was ~90 min.
[en] Objective: Previous studies have shown that the accumulation level of FMAU in tumor is proportional to its proliferation rate. This study demonstrated that 2′-deoxy-2′-[18F]fluoro-β-D-arabinofuranosyluracil ([18F]FMAU) is a promising PET probe for noninvasively monitoring the therapeutic efficacy of 6% PEGylated liposomal vinorelbine (lipo-VNB) in a subcutaneous murine NG4TL4 sarcoma mouse model. Methods: Female syngenic FVB/N mice were inoculated with NG4TL4 cells in the right flank. After tumor size reached 150 ± 50 mm3 (day 0), lipo-VNB (5 mg/kg) was intravenously administered on days 0, 3 and 6. To monitor the therapeutic efficacy of lipo-VNB, [18F]FMAU PET was employed to evaluate the proliferation rate of tumor, and it was compared with that observed from [18F]FDG/[18F]fluoroacetate PET. The expression of proliferating cell nuclear antigen (PCNA) in tumor during treatment was determined by semiquantitative analysis of immunohistochemical staining. Results: A significant inhibition (p < 0.001) in tumor growth was observed on day 3 after a single dose treatment. The tumor-to-muscle ratio (T/M) derived from [18F]FMAU-PET images of lipo-VNB-treated group declined from 2.33 ± 0.16 to 1.26 ± 0.03 after three doses of treatment, while that of the control remained steady. The retarded proliferation rate of lipo-VNB-treated sarcoma was confirmed by PCNA immunohistochemistry staining. However, both [18F]FDG and [18F]fluoroacetate microPET imaging did not show significant difference in T/M between the therapeutic and the control groups throughout the entire experimental period. Conclusion: Lipo-VNB can effectively impede the growth of NG4TL4 sarcoma. [18F]FMAU PET is an appropriate modality for early monitoring of the tumor response during the treatment course of lipo-VNB
BackgroundWe recently upgraded our [18F]fludeoxyglucose (FDG) production capabilities with the goal of futureproofing our FDG clinical supply, expanding the number of batches of FDG we can manufacture each day, and improving patient throughput in our nuclear medicine clinic. In this paper we report upgrade of the synthesis modules to the GE FASTLab 2 platform (Phase 1) and cyclotron updates (Phase 2) from both practical and regulatory perspectives. We summarize our experience manufacturing FDG on the FASTLab 2 module with a high-yielding self-shielded niobium (Nb) fluorine-18 target.
ResultsFollowing installation of Nb targets for production of fluorine-18, a 55 μA beam for 22 min generated 1330 ± 153 mCi of [18F]fluoride. Using these cyclotron beam parameters in combination with the FASTLab 2, activity yields (AY) of FDG were 957 ± 102 mCi at EOS, corresponding to 72% non-corrected AY (n = 235). Our workflow, inventory management and regulatory compliance have been greatly simplified following the synthesis module and cyclotron upgrades, and patient wait times for FDG PET have been cut in half at our nuclear medicine clinic.
ConclusionsThe combination of FASTlab 2 and self-shielded Nb fluorine-18 targets have improved our yield of FDG, and enabled reliable and repeatable manufacture of the radiotracer for clinical use.
[en] Complete text of publication follows: Objectives: No-carrier-added (n.c.a.) nonafluorobutane-1-sulphonyl [18F]fluoride (Nfl-[18F]F, [18F]1) was reported by Jelinski et al. to act as a reagent for replacement of a hydroxy group with a fluorine-18 atom (eq. 1). However, because of the n.c.a. status of [18F]1, the concentration of the in situ ester 2 is very low, making the reaction too slow for satisfactory yields of 3. Addition of carrier 1 gave excellent results. The authors produced [18F]1 from a sulphon-imide and isolated it by distillation before further reaction. Instead, we envisaged to start from nonafluorobutane-1-sulphonyl chloride (4, Nfl-Cl) without isolation. After addition of the appropriate alcohol and base the excess of Nfl-Cl (4) is expected to act as a pseudo carrier generating ester 2 also, thus increasing the latter concentration. We report here our preliminary and somewhat surprising observations concerning the reaction of Nfl-Cl (4) with [18F]fluoride. Methods: In a TRACERLabTM FX-FN synthesizer n.c.a. [18F]fluoride was conditioned either as the K[18F]F/K(222) complex (evaporation to dryness with 4.5 mg K2CO3, 12-15 mg Kryptofix) or as dry Bu4N[18F]F (using 13.6 mg Bu4NHCO3). To this was added (by helium pressure) 10 μmol of Nfl-Cl (4) or Nfl-F in 0.5 mL of acetonitrile or DMF at room temperature. The reactor was sealed and the mixture was heated at 80-100 C during 5 min. Results: Unexpectedly, upon addition of Nfl-Cl (4) to K[18F]F/K(222) an immediate emanation of volatile radioactivity (20% of total) took place, carried away before the reactor could be sealed. After heating, little or no volatile radioactivity could be released from the reactor. We hypothesized that either [18F]FCl or [18F]FClSO2 had been formed or that the desired [18F]1 (b.p. 65 C) is volatile enough to be swept away by the helium stream. We observed the same phenomenon with Nfl-F (1), which should then give [18F]F2, [18F]F2SO2 or again [18F]1. We performed two test reactions on the gaseous radioactivity from Nfl-F. (I) The volatiles were directed into the usual CHCl3/precursor solution for the synthesis of 6-[18F]fluoro-DOPA from [18F]F2 and the resulting radioactive solution was subjected to the synthesis protocol of this radiopharmaceutical. No 6-[18F]fluoro-DOPA was formed but all radioactivity volatilized immediately on the CHCl3 evaporation step after hydrolysis. (II) The volatiles were directed into a toluene solution of DBU and the appropriate hydroxy precursor 5 for [18F]DPA-714 (6) . Although Nfl-F had been shown to give good yields of DPA-714 in 10 min at room temperature not a trace of [18F]DPA-714 (6) was found with radioTLC analysis of the reaction mixture. Yet an efficient conversion of Nfl-Cl into Nfl-F has been described: Bu3HNF, acetamide, 80 C, 10 min, 100%. Aiming at conditions close to these we added Nfl-Cl (4) in DMF to Bu4N[18F]F/Bu4NHCO3 and heated for 10 min at 80 C. Again volatile radioactivity emanated. Neither these volatiles nor the activity remaining in solution could be reacted with the precursor for [18F]DPA-714 (5) hinting that no [18F]1 had been produced. Conclusions: These preliminary results seem to point to a formation of [18F]FClSO2 or [18F]F2SO2 according to eq. 2. In order to reach our goal we now envisage to isolate n.c.a. [18F]1 according to Jelinski et al. and add Nfl-Cl (4) to it afterwards
[en] An improved synthesis of 2'-[18F]-fluoro-2'-deoxy-1-β-D-arabinofuranosyl-5-iodouracil ([18F]-FIAU) has been developed. The method utilizes trimethylsilyl trifluoromethanesulfonate (TMSOTf) catalyzed coupling of 2-deoxy-2-[18F]-fluoro-1,3,5-tri-O-benzoyl-D-arabinofuranose with 2,4-bis(trimethylsilyloxy)-5-iodouracil to yield the protected dibenzoyl-[18F]-FIAU. Dibenzoyl-[18F]-FIAU was deprotected with sodium methoxide to yield a mixture of α- and β-anomers in a ratio of 1:1, which were purified by HPLC. The procedure described in this article eliminates the need for HBr activation of the sugar prior to coupling with silylated iodouracil and is suitable for automation. The total reaction time was about 110 min, starting from [18F]-fluoride. The average isolated yield of the required β-anomer was 10±6% (decay corrected) with average specific activity of 125 mCi/μmol.