Herein, we report two synthetically useful and high yielding routes to so far unknown branched γ,γ′- and δ,δ′-difluoroalkylamines that can be of interest as building-blocks for medicinal chemistry ...programs.
Application of methylaza-analog of S-adenosyl-l-methionine (MeAzaAdoMet) as a substrate for fluorinase is described. Optimal radiofluorination conditions are established and the desired 18FFDA is ...obtained with 32% yield in 180min.
•Novel substrate, methylaza-analog of SAM, was suggested for fluorinase-catalyzed radiofluorination.•Optimal reaction conditions are established.•MeAzaAdoMet was fluorinated with 18FF− ions with 32% yield.
Methylaza-analog of S-adenosyl-l-methionine (MeAzaAdoMet) was found to be a substrate for fluorinase. This is the first discovery of a new substrate for fluorinase that can be accessed synthetically in high purity. The activity of fluorinase for the new MeAzaAdoMet and 18Ffluoride ion was 32% in 180min.
Direct nucleophilic radiosynthesis of di-
tert
-butyl-(4-
18
Ffluoro-1,2-phenylene)-dicarbonate was conducted through no-carrier-added electrochemical reactions. 10 mM of triethylamine acetic acid ...(Et
3
N·3HAc) in acetonitrile was used to release
18
Ffluoride ion trapped in the quaternary ammonium anion exchange resin. The relationship between radiofluorination efficiency, concentration of the Et
3
N·3HAc, and the working potential were studied with a di-
tert
-butyl-(4-(
tert
-butyl)-1,2-phenylene)-dicarbonate substrate in nonaqueous acetonitrile solution. Radiochemical yields of 6.8 ± 1.3 % with specific activity of up to 13 GBq/µmol were achieved with a precursor concentration of 50 mM after a reaction time of 57 min at 0 °C.
Abstract Introduction Recently, a PET tracer, 9-18 Ffluoropropyl-(+)-dihydrotetrabenazine (18 FAV-133), targeting vesicular monoamine transporter 2 (VMAT2) in the central nervous system has been ...reported. It is currently under Phase II clinical trials to establish its usefulness in the diagnosis of neurodegenerative diseases including dementia with Lewy bodies and Parkinson's disease. The radiolabeling of 18 FAV-133, nucleophilic fluorination reaction and potential effects of pseudo-carrier were evaluated by in vivo biodistribution. Methods The preparation of 18 FAV-133 was evaluated under different conditions, specifically by employing different precursors (–OTs or –Br as the leaving group at the 9-propoxy position), reagents (K222/K2 CO3 vs. tributylammonium bicarbonate) and solvents (acetonitrile vs. DMSO), reaction temperature and reaction time. With optimized conditions from these experiments, radiosynthesis and purification with solid-phase extraction (SPE) of 18 FAV-133 were performed by an automated nucleophilic 18 Ffluorination module. In vivo biodistribution in mice on 18 FAV-133 purified by either HPLC (no-carrier-added) or the SPE method (containing a pseudo-carrier) was performed and the results compared. Results Under a mild fluorination condition (heating at 115°C for 5 min in dimethyl sulfoxide), 18 FAV-133 was obtained in a high yield using either –OTs or –Br as the leaving group. However, the –OTs precursor gave better radiochemical yields (>70%, thin layer chromatography analysis) compared to those of the –Br precursor. The optimized reaction conditions were successfully implemented to an automated nucleophilic fluorination module. Labeling and purification of 18 FAV133 were readily achieved via this automatic module in good radiochemical yield of 21–41% ( n =10) in 40 min. The radiochemical purity was larger than 95%. Biodistribution of SPE-purified product (containing a pseudo-carrier) in mice showed a high striatum/cerebellum ratio (4.18±0.51), which was comparable to that of HPLC-purified 18 FAV-133 (4.51±0.10). Conclusions The formation of 18 FAV-133 was evaluated under different labeling conditions. These improved labeling conditions and SPE purification were successfully implemented into an automated synthesis module. This offers a short preparation time (about 40 min), simplicity in operation and ready applicability for routine clinical operation.
Addition of secondary amine SA (dimethylamine DMA, diethylamine DEA, pyrrolidine Pyr, piperidine Pip, morpholine Mor) to pentafluoropropene PFP gives rise to generation of mixtures of two products ...(1-dialkylamine-1,3,3,3-tetrafluoropropene and
N,
N-dialkyl-1,1,3,3,3-pentafluoropropylamine) in different ratios. Those reaction mixtures, however, were found to be efficient fluorinating agents replacing hydroxyl groups in alcohols into fluorine. In general, they react with alcohols yielding corresponding fluorides, equimolar amounts of appropriate 3,3,3-trifluoropropionamide and hydrogen fluoride. Aliphatic primary alcohols including octanol and benzylic alcohol yield only alkyl fluorides. The secondary and tertiary alcohols, beside the desired fluorides, give usually considerably amount of alkenes.
Reactions of 1,1,3,3,3-pentafluoropropene (PFP) and secondary amines give mixtures of adducts (PFPDAA), which serve as an efficient fluorinating agent replacing hydroxyl groups in alcohols.
▪
A straightforward method for the preparation of no-carrier-added (n.c.a.)
18Fflumazenil via standard nucleophilic radiofluorination of the corresponding nitro-analog Ro 15-2344 has been developed. ...The labeling was performed by employing the K
18F/kryptofix complex in DMF at 160°C for 30 min and equimolar ratio K/K2.2.2
+18F
−/precursor. Under these conditions, an
18F incorporation rate into flumazenil was in the range of 55–60%. The final product was isolated by HPLC purification within a total synthesis time of 75 min and a radiochemical yield of about 30% (EOB). Human post-mortem whole-hemisphere autoradiography of brain sections demonstrated selective uptake of the radioligand in the areas of high density of the central benzodiazepine receptors (BZR). PET studies in a cynomolgus monkey and metabolite studies by HPLC demonstrated similar results by
18Fflumazenil as for
11Cflumazenil. In blocking experiments, almost all radioactivity was inhibited by the addition of unlabeled flumazenil.
18FFlumazenil is a suitable radioligand for PET assessment of the BZR.
The use of Room Temperature Ionic Liquids (RTILs) for a variety of halogen exchange (Halex) fluorination processes using alkali metal fluorides is assessed. Whilst fluorination of a range of ...halogenated substrates is possible in good yield, the utility of RTILs as reusable, inert media for such reactions is limited by the gradual decomposition of the RTIL in the presence of highly basic fluoride ion.
Noninvasive imaging in living subjects with positron emission tomography (PET) provides early detection of diseases in humans. For this application, it is necessary to prepare specific molecular ...imaging probes labeled with positron-emitting radioisotopes such as fluorine-18 for obtaining high-quality PET imaging. In this review, we describe recent trends in the F-18 radiolabeling method for the introduction of no-carrier-added fluorine-18, which was obtained from an
18
O(p,n)
18
F reaction, into a specific molecular site, which in turn is intended to serve as an imaging agent for PET study. These labeling protocols are based on ionic liquid media
18
F radiofluorination in the presence of some water, enzymatic
18
F fluorination using fluorinase in water solution, non-polar protic alcohol media
18
F radiofluorination and its mechanism, and nucleophilic
18
F fluorination of an aromatic iodonium salt precursor.
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