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18FFDDNP has been recently described as a potent tracer to image amyloid plaques in vivoby positron emission tomography. Such a tool will be advisable to diagnose patient with mild cognitive impairment, to follow the disease progression and to evaluate new therapies. To make this radiopharmacetical affordable for the clinicians, we developed an automated method for 18FFDDNP radiosynthesis using a commercial 18FFDG unit. Radiolabeling with fluorine18 was carried out by a 18Ffluorodetosylation reaction on the precursor 2162tosyloxyoethylmethylamino2naphthylethylidenemalononitrile. The reaction was performed in acetonitrile for 15 min at 90°C, and then the reaction mixture was injected into a semipreparative highpressure liquid chromatography. The desire 18FFDDNP fraction was collected, and an SPE was performed. The 18FFDDNP was formulated in a sodium chlorideethanol solution followed by a sterile filtration. Stability of 18FFDDNP was studied after 4 h and radiochemical purity of 18FFDDNP remained >98.The overall decaycorrected radiochemical yield was 15±3 n8. Radiochemical purity was >98 and the specific activity was 164±25 GBqµmol at EOS. Pharmaceutical controls, bioburden, sterility, bacterial endotoxin and residual solvent tests were performed. The results were in accordance with the European Pharmacopoeia and demonstrated our ability to produce 18FFDDNP with a pharmaceutical grade and a high reproducibility. Copyright © 2010 John Wiley & Sons, Ltd.

LBT‐999 (8‐((E)‐4‐fluoro‐but‐2‐enyl)‐3‐beta‐p‐tolyl‐8‐aza‐bicyclo[3.2.1]octane‐2‐beta‐carboxylicacid methyl ester) is a recently developed cocaine derivative belonging to a new generation of highly selective dopamine transporter (DAT) ligands (KD: 9 nM for the DAT and IC50 > 1000 nM for the serotonin and norepinephrine transporter). Initial fluorine‐18‐labelling of LBT‐999 was based on the robust and reliable two‐step radiochemical pathway often reported for such tropane derivatives, involving first the preparation of (E)‐1‐[18F]fluoro‐4‐tosyloxybut‐2‐ene followed by a N‐alkylation reaction with the appropriate nor‐tropane moiety. In the present work, a simple one‐step fluorine‐18‐labelling of LBT‐999 is reported, based on a chlorine‐for‐fluorine nucleophilic aliphatic substitution, facilitating as expected both automation and final high‐performance liquid chromatography (HPLC) purification. The process involves: (A) reaction of K[18F]F–Kryptofix®222 with the chlorinated precursor (3.5–4.5 mg) at 165°C for 10 min in DMSO (0.6 mL) followed by (B) C‐18 PrepSep cartridge pre‐purification and finally (C) semi‐preparative HPLC purification on a Waters Symmetry® C‐18. Typically, 3.70–5.92 GBq of [18F]LBT‐999 (> 95% chemically and radiochemically pure) could be obtained with specific radioactivities ranging from 37 to 111 GBq/µmol within 85–90 min (HPLC purification and Sep‐Pak‐based formulation included), starting from a 37.0 GBq [18F]fluoride batch (overall radiochemical yields: 10–16%, non‐decay‐corrected). Copyright © 2007 John Wiley & Sons, Ltd.

Several vesamicol derivatives have already been proposed for SPECT exploration of the vesicular acetylcholine transporter (VAChT) which is localized on the nerve endings of cholinergic neurons which are known to degenerate in the early stages of Alzheimer's disease. However, most of these tracers have disadvantages such as in vivo non‐specific binding, slow brain kinetics, or high toxicity. We present in this study the synthesis, the radiolabelling and the cerebral biodistribution in rats of two enantiomeric pairs of new trozamicol derivatives, potential imaging agents for the VAChT. Radiolabelled compounds were obtained with high purity and specific radioactivity. However, after i.v. injection in rats, they distributed homogeneously throughout the brain, in contrast to the reference compound IBVM which showed in the same experimental conditions a high striatum/cerebellum fixation ratio. These results demonstrate that these new compounds are unsuitable for the in vivo imaging of the VAChT using SPECT. Copyright © 2007 John Wiley & Sons, Ltd.

LBT‐999 (8‐((E)‐4‐fluoro‐but‐2‐enyl)‐3β‐p‐tolyl‐8‐aza‐bicyclo[3.2.1]octane‐2β‐carboxylic acid methyl ester) is a cocaine derivative belonging to a new generation of highly selective dopamine transporter ligands (KD:9 nM). LBT‐999 was labelled with fluorine‐18 at its fluoromethylvinyl moiety using the following two‐step radiochemical process: (a) No‐carrier‐added nucleophilic aliphatic radiofluorination from (E)‐1, 4‐ditosyloxybut‐2‐ene and the activated K[18F]F‐Kryptofix®222 complex in acetonitrile at 70°C for 10 min giving (E)‐1‐[18F]fluoro‐4‐tosyloxybut‐2‐ene, followed by (b) condensation of the latter with 3β‐p‐tolyl‐8‐aza‐bicyclo[3.2.1]octane‐2β‐carboxylic acid methyl ester in N,N‐dimethylformamide containing potassium iodide for 20 min at 90°C and (c) HPLC purification (SunFire™ C18, eluent H2O/CH3CN/TFA (72:28:0.1 (v/v/v)). Radiochemically pure (> 95%) [18F]LBT‐999 (2.03–2.96 GBq, 37–111 GBq/μmol) was obtained in 95–100 min starting from a 44.4 GBq [18F]fluoride ion production batch (4.6–6.7% non‐decay‐corrected overall yield). Copyright © 2006 John Wiley & Sons, Ltd.

In order to simplify preparation of [¹²³I]PE2I, iodogen and hydrogen peroxide were examined as oxidants for the preparation of radioiodinated PE2I, e.g. (E)-N-(3-iodoprop-2-enyl)-2β-carbomethoxy-3β-(4'-tolyl) nortropane). Among the oxidizing compounds assayed, iodogen appears to afford the best results for this purpose (high radiochemical yield, high chemical purity and a reasonable reaction time). A simplified and efficient method is described here for the preparation of [¹²³I]PE2I based on the exchange of a ¹²³I tributyl tin analogue in oxidative conditions followed by purification by solid phase extraction (SPE). Using this method, [¹²³I]PE2I was obtained with a radio-pharmaceutical yield over 60%, with chemical and radiochemical purities higher than 95% without the addition of a carrier (Na¹²⁷I) (2G Bq/nmol) or with a specific activity adjusted to 85–90 MBq/nmol in the presence of the carrier. Copyright © 2002 John Wiley & Sons, Ltd.

The serotoninergic system is involved in a variety of neurological and psychiatric disorders. Exploration of the serotonin transporters (5-HTT) in living human brain by PET would be of great value for better understanding, diagnosis and therapeutic follow up of these diseases. In order to obtain a selective radioligand to explore the 5-HTT by PET we report the synthesis of [¹¹C]N,N-dimethyl-2-(2-amino-4-iodophenylthio)-benzylamine ([¹¹C]ADAM). The precursor for labelling N-demethyl ADAM, was obtained in five steps using 2,5-dibromonitrobenzene and 2-thio-N-methylbenzamide as starting material. [¹¹C]ADAM was synthesised by N-alkylation of the precursor using [¹¹C]methyl iodide in DMF. The incorporation yield of [¹¹C]methyl iodide was in the range of 50 to 70%. Finally [¹¹C]ADAM was obtained in 30 minutes synthesis time including HPLC and with a radiochemical purity better than 99%. Copyright © 2001 John Wiley & Sons, Ltd.

Research on depression and anxiety disorders would benefit from the development of suitable radioligands for PET-imaging of the serotonin transporter. Three cocaine analogues, 2β-carbomethoxy-3β-(3'-iodo-4'-methyl, -ethyl and isopropyl phenyl)nortropane (LBT-14, EINT and LBT-44), were prepared in a three-step synthesis by 1-4 addition of the appropriate Grignard reagent to anhydroecgonine methyl ester as first step. Iodination of the phenyl ring was accomplished with a mixture of yellow mercuric oxide, perchloric acid and acetic acid followed by a solution of iodine in dichloromethane. N-desmethylation was performed by using 2,2,2-trichloroethylchloroformiate followed by treatment of zinc in acetic acid. Acidic hydrolysis of the ester functions gave the carboxylic acid analogues of LBT-14, EINT and LBT-44. The precursors were labelled with ¹¹C using [¹¹C]methyl iodide or [¹¹C] methyl triflate in dimethyl formamide (DMF) and tetrabutyl ammonium hydroxide (TBAH) as base. [¹¹C]LBT-14, [¹¹C]EINT and [¹¹C]LBT-44 were all examined in Cynomolgus monkey with PET. All three compounds entered the monkey brain to a high degree (5∽–10% of injected dose). There was a marked uptake of radioactivity in the thalamus and the brain stem, regions known to contain serotinin transporters. Pre-treatment with the selective serotonin transporter inhibitor citalopram had minor effect on the binding ratios, suggesting that none of the three examined radioligands are preferable to the previously examined non-iodinated 4'-isopropenyl analogue [¹¹C]RTI-357 for the study of the serotonin reuptake system with PET. Copyright © 2000 John Wiley & Sons, Ltd.

PE2I ((E)-N-(3-iodoprop-2-enyl)-2β-(4'-tolyl) nortropane) is a cocaine derivative belonging to a new generation of selective dopamine transporter inhibitors. Labelled with iodine-123 (half-life: 13·1 hours), PE2I has been dedicated to the diagnostics of neurodegenerative diseases such as Parkinson's disease in humans using single photon emission computed tomography. Labelled with carbon-11 (half life: 20·4 minutes), it can be used in the absolute quantification of the dopamine transporter (DAT) using the high-resolution, sensitive and non-invasive quantitative imaging technique PET (positron emission tomography). In this paper, the radiosynthesis of carbon-11 labelled PE2I was investigated and oriented towards the preparation of multi milliCuries of radiotracer. Typically, 200 to 300 mCi (7·4–11·1 GBq) of [¹¹C]PE2I were routinely obtained within 25 minutes of radiosynthesis (including HPLC purification) with specific radioactivities ranging from 0·8 to 1·2 Ci/μmol (29·4–44·4 GBq/μmol). Based on the preliminary PET experiments, it can be assumed that this radioligand would permit quantification of the DAT using PET and mathematical compartmental ligand-transporter models. Copyright © 2000 John Wiley & Sons, Ltd.

In order to study the dopamine transporter by PET, we prepared (E)-N-(3-bromoprop-2-enyl)-2β-carbomethoxy-3β-(4'-tolyl) nortropane (PE2Br) and its radiobrominated analogue, PE2Br and [⁷⁶Br]PE2Br were synthesized by bromodestannylation of the tributylstannyl derivative using either N-bromosuccinimide in THF or [⁷⁶Br]NHBr with peracetic acid as oxidant respectively. After purification by HPLC, [⁷⁶Br]PE2Br was obtained with a radiochemical yield of 80%, a radiochemical purity higher than 98% and a specific radioactivity of 20 MBq/nmol. Ex vivo autoradiographic studies in rats showed that 1 hour after i.v. injection of [⁷⁶Br]PE2Br the highest accumulation in the brain was observed in the striata whereas no accumulation was observed in any other brain region. These results can be interpreted in terms of specific binding of [⁷⁶Br]PE2Br to the dopamine transporter. Copyright © 1999 John Wiley & Sons, Ltd.

Neurokinins (NKs) are the most important of the peptides released from neuronal sensory afferents. In mammals different NKs [substance P (SP), neurokinin A (NKA) and neurokinin B (NKB)] act as neurotransmitters and neuromodulators.(1) The biological responses induced by these neuropeptides are mediated by three distinct receptors NK1, NK2 and NK3 respectively. The NK1 receptors are widely distributed throughout the CNS and peripheral nervous systems. In recent years, clinical studies with selective NK1 receptor antagonists showed results for the treatment of emesis, depression, anxiety, pain and migraine.(2) Since the discovery of the first selective non‐peptide NK1 antagonist CP‐96,345, a considerable research in this area has been developed by the pharmaceutical industry.(3) In 1995, Takeda company described a novel class of highly potent, selective, and orally active NK1 antagonists such as 6‐pyrido[3, 4‐b]pyridinecarboxamide derivatives.(4) In this series, EP 00652218 1 (Scheme 1) was shown to exhibit subnanomolar affinity (IC50: 0.21nM, in vitroinhibition of [125I]‐BH‐SP binding in human IM‐9 cells) towards the NK1 receptors. Moreover, SAR studies demonstrated that the bis (trifluoromethylbenzyl) moiety was essential for the affinity. This led us to consider that EP 00652218 1 could be a good candidate for in vivoimaging of NK1 receptors and that the design of pyridine or phenyl ring substituted analogs would retain a high affinity. In order to develop ligands that could be used either in PET or SPECT studies, we undertook the synthesis of compounds bearing an halogen atom (fluorine, bromine or iodine). In this paper we report both the synthesis and labelling of the reference EP 00652218 1 with carbon‐11 and of the analog 2 with fluorine‐18 (Schemes 1, 2 and 3).