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The lead compound of a new series of azabicyclic carbamates described by Astra Laboratories as ligands for the α7 nicotinic acetylcholine receptor subtype, namely N-(4-bromophenyl)carbamic acid quinuclidin-3-yl ester, has been labelled with carbon-11 using no-carrier-added [¹¹C]phosgene and the isocyanate pathway. Typically, 25–35 mCi (0.92–1.29 GBq) of the tracer was obtained within 30 min of radiosynthesis (HPLC purification included) with specific radioactivities ranging from 500 to 800 mCi/µmol (18.5–29.6 GBq/µmol). Biodistribution studies demonstrated a relatively good brain uptake of the compound (0.8–1.2% I.D./g tissue in various brain regions), but without preferential concentration in brain regions rich in α7-subtype nicotinic receptor (e.g. hippocampus, pons and colliculi). No specific binding could be demonstrated in pre-saturation studies performed with both the cold compound and nicotine. Therefore, this ligand is not suitable for further exploration in PET imaging. Copyright © 2001 John Wiley & Sons, Ltd.

Me-QNB (N-methyl-quinuclidin-3-yl benzilate or N-methyl-quinuclidin-3-yl diphenylhydroxy acetate) is a hydrophilic, non-metabolized and highly specific muscarinic acetylcholinergic antagonist. Using this quaternary ammonium derivative of QNB, labelled with carbon-11, a positron-emitting isotope (half-life : 20.4 minutes), the potential for quantification of myocardial muscarinic receptors in vivo using the high-resolution, sensitive and quantitative imaging technique PET (positron emission tomography) was previously demonstrated in dogs and validated in humans. In this paper, the radiosynthesis of carbon-11-labelled Me-QNB is investigated and oriented towards the preparation of multi milliCuries of radiotracer. Typically, using no-carrier-added [¹¹C]methyl triflate as the alkylating agent and 0.64 mg (1.89 µmol) of QNB as precursor for labelling at 100°C for 1 minute lead to a 48.5% +/−10% (15 runs) decay-corrected radiochemical yield (based on [¹¹C]methyl triflate). 183 mCi (+/−39) of [¹¹C]Me-QNB ([¹¹C]-1) could be synthesized in only 27 to 28 minutes after EOB and occasionally, up to 340 mCi of [¹¹C]Me-QNB ([¹¹C]-1) were obtained, corresponding to a 85% decay-corrected yield. The associated decay-corrected specific radioactivities obtained were 2658 mCi/µmol (+/−971) at EOB. Copyright © 2001 John Wiley & Sons, Ltd.

We have recently described the labeling of a natural deoxyribose phosphodiester oligonucleotide with fluorine-18 (t1/2 : 109·8 min) and demonstrated its potential for in vivo imaging in a primate PET study. We here report that the methodology employed can be reliably and routinely applied to the most popular chemical modifications: (a) full length internucleosidic phosphorothioate diester bonds deoxyribose oligonucleotides (the modification most favoured by industry for human antisense therapy), (b) hybrid methylphosphonate/phosphodiester internucleosidic bonds deoxyribose oligonucleotides and (c) 2'Methyl modified ribose oligonucleotides. The whole fluorine-18 labeling procedure allows us to obtain 15 to 21 mCi (0·55 to 0·74 GBq) of pure labeled oligonucleotides (regardless the modification of the sugar phosphate backbone) in 180 minutes with a specific radioactivity of 0·8 to 2 Ci/μmol (30 to 70 GBq/μmol) at the end of synthesis. Copyright © 2000 John Wiley & Sons, Ltd.

[¹¹C]FLB 457 is a high affinity dopamine D2 receptor radioligand that is used for visualisation and quantitation of extrastriatal dopamine D2 receptors with positron emission tomography (PET). In this study, we report a comparison regarding the specific radioactivity of [¹¹C]FLB 457 obtained by two different methods of synthesising [¹¹C]methyl iodide. In addition, the synthesis of unlabelled FLB 457 and the corresponding desmethyl-precursor, starting from commercially available material, is reported. The first method used for [¹¹C]methyl iodide synthesis was reduction of [¹¹C]CO2 with lithium aluminium hydride in tetrahydrofuran to [¹¹C]CH3OH, followed by conversion into [¹¹C]CH3I= with hydrogen iodide. The second, recently developed method uses gas phase halogenation of [¹¹C]CH4 with iodine. [¹¹C]FLB 457 was labelled with [¹¹C]methyl triflate produced on-line from [¹¹C]methyl iodide. With the first method a specific radioactivity for [¹¹C]FLB 457 of 2100 Ci/mmol (78 GBq/μmol) (n=13) at 40 min after end of bombardment (EOB) was achieved. Using the gas phase method a specific radioactivity of 3400 Ci/mmol (126 GBq/μmol) (n=7) at 40 min EOB could be obtained. The use of the gas phase method also resulted in shorter time for set-up compared to the regular method since no wet chemistry is involved in the preparation of [¹¹C]methyl iodide. Copyright © 2000 John Wiley & Sons, Ltd.

Desmethyl-raclopride was synthesized via a straightforward, three-step synthetic approach and used for the preparation of [¹¹C]raclopride from [¹¹C]methyl triflate. Conditions for the radiolabelling were optimized to obtain a simple and reproducible procedure suitable for automation. [¹¹C]Raclopride was prepared with an average radiochemical yield of 55–65% (decay corrected, based on starting [¹¹C]methyl triflate) in a total synthesis time (including purification and formulation of product) of 35 min. The radiolabelling procedure used significantly less precursor, avoided the use of DMSO, and was shorter compared to the standard radiolabelling procedure with [¹¹C]methyl iodide. Copyright © 1999 John Wiley & Sons, Ltd.

The scope of the nucleophilic aromatic substitution reaction of 2-substituted pyridines with no-carrier-added [¹⁸F]fluoride ion (half life: 110 minutes) as its [¹⁸F]FK-K222 activated complex, has been evaluated via the radiosynthesis of 2-[¹⁸F]fluoropyridine, chosen as a model reaction. The parameters studied include the influence of the leaving group in the 2 position of the pyridine ring, the quantity of the precursor used, the type of activation (conventional heating, micro- & ultrasonic wave irradiations), the solvent, the temperature and the duration of the reaction. Concerning the influence of the leaving group, 2-chloro- and 2-bromopyridine gave moderate to good fluorine-18 incorporation yields while 2-nitro- and especially 2-trimethylammonium pyridine gave excellent incorporation yields. Noteworthy, 2-iodopyridine was almost unreactive. As expected, the incorporation yield increased with the quantity of precursor used: high yields were observed from about 7 μmol of precursor. Using conventional heating and regardless of the substituent in the 2 position of the pyridine ring, the best yields for the radiosynthesis of 2-[¹⁸F]fluoropyridine were obtained when the temperature of the reaction was 180°C and the solvent DMSO. The yields for the 2-nitro- and the 2-trimethylammonium pyridine precursors were 77% and 88% respectively, after only 5 minutes of reaction and were similar to those observed at 150°C for longer reaction times. At 120°C, neither the 2-chloro- nor the 2-bromopyridine gave any incorporation. Using microwave irradiations, excellent incorporation yields (96%) were observed for the 2-trimethylammonium pyridine from 1 minute of reaction at 100 Watt in DMSO. Concerning the 2-chloro-, 2-bromo and 2-nitropyridine, the use of 100 Watt microwave irradiations for 2 minutes gave yields comparable to those obtained for 10 minutes of conventional heating at 180°C, 22%, 71% and 88% respectively. No incorporation at all of the radioactivity could be detected when ultrasonic waves were applied, even with long reaction time and high power. Copyright © 1999 John Wiley & Sons, Ltd.

This paper reports the synthesis of 2‐fluoro‐3‐[2(S)‐2‐azetidinylmethoxy]pyridine and its radiolabeling with fluorine‐18 ([18F]FK‐K222) by nucleophilic aromatic nitro‐to‐fluoro substitution in DMSO by conventional heating at 150°C for 20 min or by microwave activation at 100 Watt for 1 min. This fluoro compound is a closely related analog of the high affinity nicotinic ligand A‐85380 (3‐[2(S)‐2‐azetidinylmethoxy]pyridine). This compound is the lead compound of a novel 3‐pyridyl ether series of new nAChR ligands recently published, and possesses not only subnanomolar affinity, comparable to that of epibatidine, for the α4β2 subtype, but also a weaker affinity for the other subtypes of nAChRs. 110–140 mCi (4.1–5.2 GBq) of pure 2‐[18F]fluoro‐3‐[2(S)‐2‐azetidinylmethoxy]pyridine ([18F]fluoro‐A‐85380) could be obtained in less than 2 hours, with specific radioactivities of 3–5 Ci/μmol (111–185 GBq/μmol) calculated for End of Bombardment (or 1.5–2.5 Ci/μmol (55.5–92.5 GBq/μmol) at End of Synthesis) for a 20 μA, 30 min (36000 μC) irradiation of a 95% enriched [18O]water target with a 16 MeV proton beam [18O(p,n)18F]. Yields (with respect to [18F]fluoride ion): decay‐corrected 49–64%; non‐decay‐corrected 25–33%. Total synthesis time from EOB: 105–110 min (this includes the recovery of the [18F]fluoride ion from the target and the [18F]FK‐K222‐complex preparation). Preliminary results in rats showed a substantial uptake of the ligand in the thalamus (1% I.D./g tissue at 30 min) while the cerebellar uptake was 2‐fold lower. Thalamic uptake was reduced by 75–85% following a pre‐treatment with nicotine, cytisine, epibatidine or fluoro‐A‐85380. The full pharmacological profile and the potential for eventual clinical applications of this ligand as a tracer for PET experiments are currently under investigation. © 1998 John Wiley & Sons, Ltd.

This paper describes an original general method for the synthesis of oligodeoxynucleotides (ODNs) carrying the positron emitter 18F. The labeling strategy developed is simple, reliable, independent of backbone modifications and base sequence. It should be of general applicability for the labeling of natural or modified ODN, provided that the latter bear a phosphorothioate group at their 3′ end, and it should be easily transposable to other radiohalogenes such as 76Br or 123I. The methodology we developed uses recently preparative‐scale commercially available 3′‐phosphorothioate oligodeoxynucleotides and is based on the efficient coupling reaction of oligodeoxynucleotides, containing a single phosphorothioate monoester, and N‐(4‐radiohalobenzyl)‐2‐bromoacetamide. Yields of 40–45% (decay corrected) of pure [18F]N‐(4‐fluorobenzyl)‐2‐(ACCGATCCG3′‐ps)‐acetamide [18F]‐(1) (around 30 mCi or 1.1 GBq) were obtained for the whole synthetic procedure (220 minutes) with respect to [18F]fluoride ion, with specific radioactivities as high as 3 Ci/μmole (111 TBq/μmol) calculated for End of Bombardment (or 750 mCi/μmole (28 TBq/μmol) at End of Synthesis) for a 15 μA, 60 min (54000 μC) irradiation of a 50% [18O]‐enriched water target with a 16 MeV proton beam [18O(p,n)18F]. © 1997 John Wiley & Sons, Ltd.

This paper describes an original general method for the synthesis of oligodeoxynucleotides (ODNs) carrying the positron emitter ¹⁸F. The labeling strategy developed is simple, reliable, independent of backbone modifications and base sequence. It should be of general applicability for the labeling of natural or modified ODN, provided that the latter bear a phosphorothioate group at their 3’ end, and it should be easily transposable to other radiohalogenes such as ⁷⁶Br or ¹²³I. The methodology we developed uses recently preparative-scale commercially available 3'-phosphorothioate oligodeoxynucleotides and is based on the efficient coupling reaction of oligodeoxynucleotides, containing a single phosphorothioate monoester, and N-(4-radiohalobenzyl)-2-bromoacetamide. Yields of 40–45% (decay corrected) of pure [¹⁸F]N-(4-fluorobenzyl)-2-(ACCGATCCG^3'-ps)-acetamide [¹⁸F]-(1) (around 30 mCi or 1.1 GBq) were obtained for the whole synthetic procedure (220 minutes) with respect to [¹⁸F]fluoride ion, with specific radioactivities as high as 3 Ci/μmole (111 TBq/μmol) calculated for End of Bombardment (or 750 mCi/μmole (28 TBq/μmol) at End of Synthesis) for a 15 μA, 60 min (54000 μC) irradiation of a 50% [¹⁸O]-enriched water target with a 16 MeV proton beam [¹⁸O(p,n)¹⁸F]. © 1997 John Wiley & Sons, Ltd.