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Upregulation of the cannabinoid type 2 receptors (CB2R) unveils inflammation processes of pathological disorders, such as cancer, pain, or neurodegenerative diseases. Among others, CB2R agonist A-836339 has been labeled with carbon-11 for PET imaging of the CB2R and displayed promising results in a mouse model of Alzheimer’s disease. The aim of the present work was to develop fluorinated analogs of A-836339 for labeling with fluorine-18 to design a new PET tracer for CB2R imaging. Seven fluorinated analogs of A-836339 were synthesized in two to three steps and their binding affinities and selectivities for both the human and the mouse CB2R were measured as well as their early ADME profiles. Among them, compound 2f(KihCB2R= 0.1 nM, KihCB1R/KihCB2R= 300) displayed high affinity and selectivity for CB2R but also promising lipophilicity, kinetic solubility, and membrane permeation properties and was further selected for in vitrometabolism studies. Incubation of 2fwith human or rat liver microsomes followed by LC/MS analysis revealed the presence of six different metabolites mainly resulting from oxidation reactions. A tosylated precursor of 2fwas synthesized in two steps and radiolabeled with fluorine-18 to afford [18F]2fin 15 ± 5% radiochemical yield and a molar activity of 110 ± 30 GBq/μmol. Autoradiographies of rat spleen and biodistribution studies in healthy rats including pretreatments with either CB2R or CB1R-specific compounds suggested that [18F]2fis a specific tracer for the CB2R in vivo. We have therefore demonstrated here that [18F]2fis a promising novel tracer for imaging CB2R in vivousing PET. Further investigation in animal models of inflammation will follow.

[18F]DPA-714 [N,N-diethyl-2-(2-(4-(2[18F]-fluoroethoxy)phenyl)5,7dimethylpyrazolo[1,5a]pyrimidin-3-yl)acetamide] is a new radioligand currently used for imaging the 18-kDa translocator protein in animal models of neuroinflammation and recently in humans. The biodistribution by positron emission tomography (PET) in baboons and the in vitro and in vivo metabolism of [18F]DPA-714 were investigated in rats, baboons, and humans. Whole-body PET experiments showed a high uptake of radioactivity in the kidneys, heart, liver, and gallbladder. The liver was a major route of elimination of [18F]DPA-714, and urine was a route of excretion for radiometabolites. In rat and baboon plasma, high-performance liquid chromatography (HPLC) metabolic profiles showed three major radiometabolites accounting for 85% and 89% of total radioactivity at 120 minutes after injection, respectively. Rat microsomal incubations and analyses by liquid chromatography–mass spectrometry (LC-MS) identified seven metabolites, characterized as O-deethyl, hydroxyl, and N-deethyl derivatives of nonradioactive DPA-714, two of them having the same retention times than those detected in rat and baboon plasma. The third plasma radiometabolite was suggested to be a carboxylic acid compound that accounted for 15% of the rat brain radioactivity. O-deethylation led to a nonradioactive compound and [18F]fluoroacetic acid. Human CYP3A4 and CYP2D6 were shown to be involved in the oxidation of the radioligand. Finally an easy, rapid, and accurate method—indispensable for PET quantitative clinical studies—for quantifying [18F]DPA-714 by solid-phase extraction was developed. In vivo, an extensive metabolism of [18F]DPA-714 was observed in rats and baboons, identified as [18F]deethyl, [18F]hydroxyl, and [18F]carboxylic acid derivatives of [18F]DPA-714. The main route of excretion of the unchanged radioligand in baboons was hepatobiliary while that of radiometabolites was the urinary system.

Tumor-associated inflammation has been linked to angiogenesis, metastasis and poor prognosis. The 18 kDa translocator protein (TSPO), also known as the peripheral benzodiazepine receptor (PBR), is expressed in activated immune cells such as macrophages, but also in a number of cancer cell lines such as those of breast cancer. There is an increasing clinical interest in TSPO expression as it has been proposed as a poor prognostic factor for survival in lymph-node negative breast cancer patients. This study aims to assess of the presence of neoplastic cell-associated TSPO and tumor macrophage-associated TSPO in mouse xenografts generated from the MDA-MB-231 and the MCF-7 breast cancer cell lines, as well as 25 different breast tumors originally derived from patient-tissue but propagated in mice using two antibodies, each specific to either the human or the murine form of TSPO. Autoradiography with the TSPO ligand [18F]DPA-714 and immunohistochemistry were also performed on the excised tumor tissues from the MDA-MB-231, MCF-7 and one of the patient-derived xenografts (HBCx-12B). High TSPO expression (either cancer or stromal cell-associated, or both) was measured in 20/25 (80%) of the patient-derived breast cancer xenografts. [18F]DPA-714 showed displaceable binding to both the human and murine TSPO on tumor tissue sections. Immunohistochemistry demonstrated that a significant portion of the tumor stromal TSPO expression colocalized with F4/80 positive macrophages cells. This study constitutes a first report of the tumor TSPO expression by mixed cell populations, and it may have important implications for cancer biology as well as for the development of imaging and therapeutic ligands targeted to TSPO.

In order to perform in vivoimaging of the NR2B NMDA receptor system by positron emission tomography, a NR2B selective NMDA receptor antagonist has been labelled with carbon11 halflife: 20 min. N44fluorobenzylpiperidin1ylN′2oxo1,3dihydrobenzimidazol5yloxamide has been described demonstrating high affinity and selectivity for the NR2B receptors IC50of 5 nM in 3HRo25,6981 binding assay. The labelling precursor and the reference compound were synthesized by coupling the 44fluorobenzylpiperidine with the corresponding oxalamic acid. The reaction of 11Cphosgene with phenylenediamine precursor led the formation of the 11Cbenzimidazolone ring present on the ligand. The labelling occurred in THF or acetonitrile and the decay corrected radiochemical yield was 30–40 from the produced 11Cmethane. HPLC purification and formulation led to 2.6–3.7 GBq 70–100 mCi of radioligand within 30–35 min. The specific radioactivity was 72–127 GBqµmol 2–3.4 Ciµmol at the end of synthesis. Copyright © 2009 John Wiley & Sons, Ltd.

PBR111 26chloro243fluoropropoxyphenylimidazo1,2apyridin3ylN,Ndiethylacetamide is a novel, reported, highaffinity and selective ligand for the translocator protein 18 kDa. PBR111 has been labelled with fluorine18 halflife: 109.8 min using our ZymateXP robotic system. The process involves A a simple onestep tosyloxyforfluorine nucleophilic aliphatic substitution performed at 165°C for 5 min in DMSO using K18FFKryptofix®222 and 6.8–7.6 µmol of the corresponding tosylate as precursor for labelling followed by B C18 PrepSep cartridge prepurification and C semipreparative HPLC purification on a Waters Symmetry®C18. Up to 4.8 GBq 130 mCi of 18FPBR111 could be obtained with specific radioactivities ranging from 74 to 148 GBqµmol 2–4 Ciµmol in 75–80 min HPLC purification and SepPak®based formulation included, starting from a 37.0 GBq 1.0 Ci 18Ffluoride batch. Overall nondecaycorrected isolated yields were 8–13 13–21 decaycorrected. Copyright © 2008 John Wiley & Sons, Ltd.

FPyKYNE 2fluoro3pent4yn1yloxypyridine is a novel fluoropyridinebased structure, designed for the fluorine18 labelling of macromolecules using coppercatalysed Huisgen 1,3dipolar cycloaddition click chemistry. FPyKYNE nonlabelled as reference, as well as the 2bromo, 2nitro and 2trimethylammonium analogues as precursors for labelling with fluorine18, was synthesized in 44, 95, 60 and 41, respectively, from commercially available 5chloropent1yne and the appropriate 2substituted3hydroxypyridines. 18FFPyKYNE was synthesized in one single radiochemical step by reaction of nocarrieradded K18FFKryptofix®222 DMSO, 165°C, 3–5 min followed by C18 SepPak cartridge prepurification and finally semipreparative HPLC purification on a Hewlett Packard SiO2Zorbax®RxSIL. Using the 2nitropyridine or the pyridin2yltrimethylammonium trifluoromethanesulphonate precursor for labelling 30 and 10 µmol, respectively, incorporation yields up to 90 were observed and 7.0–8.9 GBq 190–240 mCi of 18FFPyKYNE 18F1 could be isolated within 60–70 min HPLC purification included, starting from a 37.0 GBq 1.0 Ci 18Ffluoride batch overall decaycorrected and isolated yields: 30–35. Copyright © 2008 John Wiley & Sons, Ltd.

Recently, a novel series of 2phenylpyrazolo1,5apyrimidineacetamides has been reported as selective ligands of the translocator protein 18 kDa. Within this series, DPA714 N,Ndiethyl2242fluoroethoxyphenyl5,7dimethylpyrazolo1,5apyrimidin3ylacetamide, Ki7.0 nM is a compound, which had been designed with a fluorine atom in its structure, allowing labelling with fluorine18 halflife: 109.8 min and in vivoimaging using positron emission tomography. DPA714 and its tosyloxy derivative N,Ndiethyl2242toluenesulfonyloxyethoxyphenyl5,7dimethylpyrazolo1,5apyrimidin3ylacetamide as precursor for the labelling with fluorine18 were synthesized in two steps from DPA713 N,Ndiethyl224methoxyphenyl5,7dimethylpyrazolo1,5apyrimidin3ylacetamide and obtained in 32 and 42 yields, respectively. 18FDPA714 was synthesized using a simple onestep process a tosyloxyforfluorine nucleophilic aliphatic substitution, which has been fully automated on our ZymateXP robotic system. It involves: A reaction of K18FFKryptofix®222 with the tosyloxy precursor 4.5–5.0 mg, 8.2–9.1 µmol at 165°C for 5 min in dimethyl sufloxide 0.6 mL followed by B C18 PrepSep cartridge prepurification and finally C semipreparative highperformance liquid chromatography HPLC purification on a Waters XTerra™ RP18. Typically, 5.6–7.4 GBq of 18FDPA714 >95 chemically and radiochemically pure could be obtained with specific radioactivities ranging from 37 to 111 GBqµmol within 85–90 min HPLC purification and SepPak®based formulation included, starting from a 37 GBq 18Ffluoride batch overall nondecaycorrected and isolated radiochemical yield: 15–20. Copyright © 2008 John Wiley & Sons, Ltd.

Within a novel series of 2‐oxazolidinones developed in the past by Sanofi‐Synthélabo, SL25.1188 ((S)‐5‐methoxymethyl‐3‐[6‐(4,4,4‐trifluorobutoxy)benzo[d]isoxazol‐3‐yl]oxazolidin‐2‐one), a compound that inhibits selectively and competitively MAO‐B in human and rat brain (Ki values of 2.9 and 8.5 nM for MAO‐B, respectively, and ED50 (rat): 0.6 mg/kg p.o.), was considered an appropriate candidate for imaging this enzyme with positron emission tomography. SL25.1188 was labelled with carbon‐11 (T1/2: 20.38 min) in one chemical step using the following process: (i) reaction of [11C]phosgene with the corresponding ring‐opened precursor (1.2–2.5 mg) at 100°C for 2 min in dichloromethane (0.5 mL) followed by (ii) concentration to dryness of the reaction mixture and finally (iii) semi‐preparative HPLC purification on a Waters Symmetry® C18. A total of 300–500 MBq of [11C]SL25.1188 (>95% chemically and radiochemically pure) could be obtained within 30–32 min (Sep‐pak‐based formulation included) with specific radioactivities ranging from 50 to 70 GBq/µmol (3.5–7% decay‐corrected radiochemical yield, based on starting [11C]CH4). Copyright © 2008 John Wiley & Sons, Ltd.

Small interfering RNAs (siRNAs), a class of macromolecules constituted by the association of two single‐stranded ribonucleic acids of short sequences, have been labelled with the positron‐emitter fluorine‐18 (T1/2: 109.8 min). The strategy involves (1) prosthetic conjugation of a single‐stranded oligonucleotide with [18F]FPyBrA (N‐[3‐(2‐[18F]fluoropyridin‐3‐yloxy)‐propyl]‐2‐bromoacetamide) followed by (2) formation of the target duplex by annealing with the complementary sequence, therefore, permitting parallel and combinatorial preparation of [18F]siRNAs. Pure fluorine‐18‐labelled siRNAs (0.55–1.11 GBq, specific activity: 74–148 GBq/µmol at EOB) could be obtained within 165 min starting from 37.0 GBq of starting [18F]fluoride (1.5–3.0%, non‐decay‐corrected isolated yields). Copyright © 2007 John Wiley & Sons, Ltd.

The Service Hospitalier Frédéric Joliot (SHFJ) (CEA‐Orsay, France) has been a stimulating interdisciplinary research platform in medical imaging for almost half a century and particularly in the field of positron emission tomography (PET). In this context, PET chemistry, the driving force in molecular imaging, has occupied the front stage, especially where it concerns the short‐lived radioisotopes carbon‐11 and fluorine‐18. In this review, important marks left by the SHFJ actors over the years will be highlighted. Copyright © 2007 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.

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.

2‐exo‐(2′‐Fluoro‐3′‐(4‐fluorophenyl)‐pyridin‐5′‐yl)‐7‐azabicyclo[2.2.1]heptane (F2PhEP), a novel, epibatidine‐based, α4β2‐selective nicotinic acetylcholine receptor antagonist of low toxicity, as well as the corresponding N‐Boc‐protected chloro‐ and bromo derivatives as precursors for labelling with fluorine‐18 were synthesized from 7‐tert‐butoxycarbonyl‐7‐azabicyclo[2.2.1]hept‐2‐ene in 13, 19 and 8% overall yield, respectively. [18F]F2PhEP was prepared in 8–9% overall yield (non‐decay‐corrected) using 1 mg of the bromo derivative in the following two‐step radiochemical process: (1) no‐carrier‐added nucleophilic heteroaromatic ortho‐radiofluorination with the activated K[18F]F‐Kryptofix®222 complex in DMSO using microwave activation at 250 W for 90 s, followed by (2) quantitative TFA‐induced removal of the N‐Boc protective group. Radiochemically pure (>95%) [18F]F2PhEP (1.48–1.66 GBq, 74–148 GBq/µmol) was obtained after semi‐preparative HPLC (Symmetry® C18, eluent aqueous 0.05 M NaH2PO4 CH3CN: 78/22 (v:v)) in 75–80 min starting from an 18.5 GBq aliquot of a cyclotron‐produced [18F]fluoride production batch. Copyright © 2006 John Wiley & Sons, Ltd.

In the aim to develop an efficient fluorinated probe for positron emission tomography (PET) exploration of the dopamine transporter (DAT), we studied several in vitro and in vivo characteristics of the phenyltropane derivative (E)-N-(4-fluorobut-2-enyl)-2beta-carbomethoxy-3beta-(4'-tolyl)nortropane (LBT-999). In vitro on rat striatal membrane, [(3)H]LBT-999 bound to a single site with a K(d) of 9 nM, B(max) of 17 pmol/mg protein, and a very high selectivity for the DAT [IC(50) for 1-{2-[bis-(4-fluorophenyl)-methoxy]ethyl}-4-(3-phenylpropyl)piperazine (GBR 12909) and (E)-N-(3-iodoprop-2-enyl)-2beta-carbomethoxy-3beta-(4'-methylphenyl)nortropane (PE2I): 2.4 and 18 nM, respectively; IC(50) for paroxetine, citalopram, N,N-dimethyl-2-(2-amino-4-methylphenyl thio)benzylamine, nisoxetine, and desipramine >1 muM]. In vitro on post-mortem human brain sections, LBT-999 bound with high intensity to the caudate-putamen, weakly to the thalamus, and not in the neocortex and cerebellum. This binding was totally abolished in the presence of PE2I. Ex vivo cerebral biodistribution of [(11)C]LBT-999 in rats showed striatum/cerebellum radioactivity ratios of 18 and 25 at 30 and 60 min postinjection, respectively. This accumulation was strongly prevented by preinjection of GBR 12909, whereas paroxetine and nisoxetine had no effect. An in vivo kinetic PET study in three baboons showed a fast and very high uptake in the striatum, with a plateau at 30 min postinjection and a maximal putamen/cerebellum ratio of 30. Taken together, these findings demonstrate that LBT-999 is a highly promising agent for in vivo exploration of the DAT. This probe is currently labeled with (18)F for further characterizations.

The reduction of [11C]carbon dioxide to [11C]methanol with lithium aluminium hydride (LiAlH4) and subsequent conversion into [11C]methyl iodide is a standard way of producing the latter precursor for radiolabelling. However, it suffers from appreciable losses by incomplete reduction giving [11C]formate. We show that samarium diiodide (SmI2) can be used to improve the yield of [11C]methanol by its ability to efficiently reduce [11C]formate to [11C]methanol. This can be done either by making [11C]formate intentionally and treating it with SmI2 or by treating the LiAlH4‐reduced [11C]CO2 with SmI2. In the latter approach, sodium thiosulphate has a similar effect as SmI2. Hydriodic acid was also shown to exert some reducing action on [11C]formate too. [11C]Carbonate is reduced to a small extent by SmI2 under the mild conditions employed. In contrast to the very easy [11C]formate reduction, SmI2 had little effect on [11C]acetate and practically no [11C]ethanol could be produced. Copyright © 2006 John Wiley & Sons, Ltd.

The blood-brain barrier (BBB) permeabilities of 11 compounds were measured both in vitro with a newly developed coculture-based model of human BBB and in vivo with positron emission tomography (PET). The 11 compounds were fluoropyridinyl derivatives labeled with the positron-emitter fluorine-18, [(18)F]F-A-85380 [2-[(18)F]fluoro-3-[2(S)-2 azetidinylmethoxy]pyridine], and 10 selected N-substituted-azetidinyl and pyrrolidinyl closely related [(18)F]fluoropyridinyl derivatives (including [N'-aromatic/aliphatic]-thioureas, -ureas, and -amides). The in vitro BBB model, a new coculture system of primary human brain endothelial cells and astrocytes, was used to measure the permeability coefficient for each compound. Dynamic PET studies were performed in rats with the same compounds, and a two-compartment model analysis was used to calculate their in vivo permeability coefficients. The 11 derivatives differed in their degree of BBB passage and transport mechanism. The analysis of PET data showed a significant cerebral uptake for six derivatives, for which the in vitro evaluation indicated active influx or free diffusion. Five derivatives displayed low in vivo cerebral uptake, in agreement with the observation of an in vitro active efflux. Overall, there was a remarkable correlation between the in vitro and in vivo permeability coefficients (r = 0.99). This double study proves a close correlationship between the assessment of the BBB passage in vitro and in vivo. The in vitro model of human BBB offers the possibility of subtle discrimination of various BBB permeability degrees and transport mechanisms. Conversely, small animal PET imaging appears suitable to screen directly in vivo brain targeting of drugs or radiopharmaceutical candidates.

1,1′‐Methylene‐di‐(2‐naphthol) (ST1859), a candidate drug for the treatment of Alzheimer's disease, was radiolabelled with carbon‐11 with the aim to perform PET microdosing studies in humans. The radiosynthesis was automated in a commercial synthesis module (Nuclear Interface PET tracer synthesizer) and proceeded via reaction of [11C]formaldehyde with 2‐naphthol. [11C]formaldehyde was prepared by catalytic dehydrogenation of [11C]methanol (conversion yield: 48±11% (n = 19)) employing a recently developed silver‐containing ceramic catalyst. Starting from 69±3 GBq of [11C]carbon dioxide (n = 19), 4±1 GBq of [11C]ST1859 (decay‐corrected to the end of bombardment), readily formulated for intravenous administration, could be obtained in an average synthesis time of 38 min. The specific radioactivity of [11C]ST1859 at the end of synthesis exceeded 32 GBq/µmol. Copyright © 2005 John Wiley & Sons, Ltd.

The in vivo characteristics of [11C]befloxatone were assessed in myocardium of rats and monkeys. A complete multicompartmental model was developed to quantify monkey cardiac monoamine oxidase A (MAO-A) binding sites using positron emission tomography (PET) and was applied to assess the acute effects of inhalation of tobacco smoke. Unknown compounds contained in tobacco smoke inhibit brain MAO. In vitro, befloxatone inhibits selectively, competitively, and reversibly MAO-A in human tissues. [11C]Befloxatone (1.85 MBq) was i.v. injected into rats. Animals were sacrificed, dissected, and samples were assessed for radioactivity. Another group of rats was pretreated with clorgyline (10 mg/kg i.v.). Monkeys were injected with [11C]befloxatone (222-370 MBq), and the chest was imaged with PET for 2 h. Presaturation and displacement experiments were performed using unlabeled befloxatone. For quantification of myocardial binding sites (Bmax), [11C]befloxatone was first injected as a tracer dose (2.7-9.3 nmol) and 20 min later injected as a mixture of labeled and unlabeled befloxatone (labeled, 10.3-41.9 nmol; unlabeled, 407-765 nmol). In rodents, cardiac uptake was high (3.39 +/- 0.5% injected dose/g tissue) and strongly inhibited (80%) by clorgyline. In monkeys, administration of unlabeled befloxatone displaced 85% of cardiac radioactivity. Bmax was found to be 208 +/- 13 pmol ml(-1) tissue. Inhalation of tobacco smoke decreased Bmax: 150 +/- 6.2 pmol ml(-1), whereas nicotine did not. [11C]Befloxatone allows a good visualization of the heart. Cardiac MAO-A Bmax was quantified and a clear effect of acute inhalation of tobacco smoke was evidenced. Therefore, a single cigarette can interfere with the cardiac turnover of catecholamines.

[2‐(3,4‐Dihydro‐1H‐isoquinolin‐2‐yl)‐pyridin‐4‐yl]‐dimethylamine, Ro‐647312 (1) represents a new novel class of NR1/2B subtype selective NMDA ligand. Ro‐647312 has been radiolabelled with carbon‐11 using [11C]methyl triflate from the nor‐methyl compound 2. The reaction was performed in acetone as solvent using aqueous NaOH as base. Following HPLC purification [11C]Ro‐647312 ([11C]‐1) was obtained in 6.9–9.2% (n = 3) radiochemical yield decay‐corrected based on starting [11C]CO2, with specific radioactivity measured at the end of the radiosynthesis ranging from 1.0 to 3.5 Ci/µmol (37–129 GBq/µmol). Radiochemical and chemical purities were assessed as >99 and >95%, respectively. Following i.v. injection of [11C]‐1 in rat, the distribution of radioactivity was homogeneous in all brain structures and did not correlate with the known distribution of NR2B subunits. The radioactivity observed in plasma was also higher than any brain structure throughout the time course of the experiment. [11C]‐1 does not possess the required properties for imaging NMDA receptors using positron emission tomography. Copyright © 2004 John Wiley & Sons, Ltd.

[11C]Formic acid can be produced from no-carrier-added [11C]carbon dioxide reliably and instantaneously in almost quantitative radiochemical yield using lithium triethylborohydride in THF. It can react, either on a solid support or as its non-hydrolysed LiEt3B-adduct, with a complex formed from hexachloroacetone and triphenylphosphine in THF at room temperature to give, again almost quantitatively, [11C]formyl chloride. The latter decomposes instantaneously to give [11C]carbon monoxide, providing an interesting alternative for current methods of [11C]carbon monoxide production in radiopharmaceutical chemistry. [11C]Formyl chloride has also potential in low-temperature N-formylation.

The false adrenergic neurotransmitter [¹¹C]meta-hydroxyephedrine ([¹¹C]HED) is currently the PET tracer of choice for assessment of myocardial sympathetic innervation. The molecule is metabolised in the 4-position of the aromatic ring. The resulting radiolabelled metabolites need to be measured in order to obtain an arterial input function. Our aim was the development of a PET tracer with an increased metabolic stability relative to [¹¹C]HED. We selected 4-methylmetaraminol as a candidate molecule for radiolabelling with ¹¹C (t1/2 20.4 min). Our radiosynthetic approach towards 4-[¹¹C]methylmetaraminol involved a palladium-catalyzed cross-coupling reaction of a protected 4-trimethylstannyl derivative of metaraminol with [¹¹C]methyl iodide followed by removal of the protective groups. 4-[¹¹C]methylmetaraminol was obtained in a final decay-corrected radiochemical yield of 20–25% within a synthesis time of 60–80 min. The specific radioactivity at the end of the synthesis ranged from 18–37 to GBq/μmol. The unlabelled reference molecule, 4-methylmetaraminol, was prepared in a 5-step synthesis starting from metaraminol. A biological evaluation of 4-[¹¹C]methylmetaraminol is in progress and the results will be reported elsewhere. Copyright © 2002 John Wiley & Sons, Ltd.

Purpose. To compare the pharmacokinetics and bioavailability of an oligonucleotide delivered in a free form or using cationic or anionic synthetic carrier systems. Methods. Whole body dynamic quantitative imaging and metabolism of a HIV antisense oligonucleotide intravenously administered either free or incorporated into synthetic carriers were compared in baboons, using non invasive positron emission tomography and an enzyme-based competitive hybridization assay, respectively. Results. In its free form, the oligonucleotide showed high liver and kidney concentration, rapid plasmatic degradation and elimination from the body. Use of a cationic vector slightly protected the oligonucleotide against degradation and enhanced uptake by the reticulo-endothelial system. In contrast, the anionic vector dramatically enhanced the uptake in several organs, including the lungs, spleen and brain, with a prolonged accumulation of radioactivity in the brain. Using this vector, intact oligonucleotide was detected in plasma for up to two hours after injection, and the T1/2β and distribution volume increased by 4- and 7-fold, respectively. No evidence of toxicity was found after a single dose administration. Conclusions. The anionic vector improves significantly the bioavailability and the pharmacokinetics of the oligonucleotide, and is a promising delivery system for in vivoadministration of therapeutic nucleic acids.

Positron emission tomography (PET) coupled to 6-[18F]Fluoro-L-Dopa (18F-Dopa) remains the gold standard for assessing dysfunctionality concerning the dopaminergic nigrostriatal pathway in Parkinson's disease and related disorders. The use of ligands of the dopamine transporters (DAT) is an attractive alternative target; consequently, the current aim was to validate one of them, 11C-PE2I, using a multiinjection modeling approach allowing accurate quantitation of DAT densities in the striatum. Experiments were performed in three controls, three MPTP-treated (parkinsonian) baboons, and one reserpine-treated baboon. 11C-PE2I B′max values obtained with this approach were compared with 18F-Dopa input rate constant values (Ki), in vitroBmax binding of 125I-PE2I, and the number of dopaminergic neurons in the substantia nigra estimated postmortem by stereology. In the caudate nucleus and putamen, control values for 11C-PE2I B'max were 673 and 658 pmol/mL, respectively, whereas it was strongly reduced in the MPTP-treated (B′max = 26 and 36 pmol/mL) and reserpine-treated animals (B′max = 338 and 483 pmol/mL). In vivo11C-PE2I B′max values correlated with 18F-Dopa Ki values and in vitro125I-PE2I Bmax values in the striatum and with the number of nigral dopaminergic neurons. Altogether, these data support the use of 11C-PE2I for monitoring striatal dopaminergic disorders and the effect of potential neuroprotective strategies.

Metaraminol is a norepinephrine analogue which is transported with high affinity by the uptake-1 mechanism of the sympathetic nerve terminal. Radiolabelled metaraminol and analogues are promising radiotracers to assess the integrity of the myocardial nerve system. The bromo analogues, 4- and 6-bromometaraminol, were synthesized from commercially available metaraminol bitartrate. Structural assignments were made by 2D-NMR experiments. 4- and 6-[⁷⁶Br]Bromometaraminol were prepared from N-Boc-metaraminol using [⁷⁶Br]NH4Br and peracetic acid as the brominating agent. The total radiochemical yield based on starting [⁷⁶Br]NH4Br was 17% and 38%, non-decay-corrected, for derivative 4-[⁷⁶Br]bromometaraminol and 6-[⁷⁶Br]bromometaraminol, respectively, in a synthesis time of 3.5 hours including the preparation of [⁷⁶Br]NH4Br. The specific radioactivity obtained for both radiotracers was 130 mCi/μmol (4.8 GBq/μmol). Tissue distribution studies were performed in rats and revealed a low cardiac uptake for both derivatives. These preliminary results suggest that neither 4- nor 6-[⁷⁶Br]bromometaraminol are suitable radiotracers to study the myocardial norepinephrine neuronal reuptake system with Positron Emission Tomography. © 1997 John Wiley & Sons, Ltd.

Metaraminol is a norepinephrine analogue which is transported with high affinity by the uptake‐1 mechanism of the sympathetic nerve terminal. Radiolabelled metaraminol and analogues are promising radiotracers to assess the integrity of the myocardial nerve system. The bromo analogues, 4‐ and 6‐bromometaraminol, were synthesized from commercially available metaraminol bitartrate. Structural assignments were made by 2D‐NMR experiments. 4‐ and 6‐[76Br]Bromometaraminol were prepared from N‐Boc‐metaraminol using [76Br]NH4Br and peracetic acid as the brominating agent. The total radiochemical yield based on starting [76Br]NH4Br was 17% and 38%, non‐decay‐corrected, for derivative 4‐[76Br]bromometaraminol and 6‐[76Br]bromometaraminol, respectively, in a synthesis time of 3.5 hours including the preparation of [76Br]NH4Br. The specific radioactivity obtained for both radiotracers was 130 mCi/μmol (4.8 GBq/μmol). Tissue distribution studies were performed in rats and revealed a low cardiac uptake for both derivatives. These preliminary results suggest that neither 4‐ nor 6‐[76Br]bromometaraminol are suitable radiotracers to study the myocardial norepinephrine neuronal reuptake system with Positron Emission Tomography. © 1997 John Wiley & Sons, Ltd.

Carbon‐11‐labelled (S)‐5‐methoxymethyl‐3‐[6‐(4,4,4‐trifluorobutoxy)benzo[d]isoxazol‐3‐yl]oxazolidin‐2‐[11C]‐one ([11C]SL25.1188), a promising reversibly binding radiotracer for imaging central monoamine oxidase B, was rapidly prepared via an intramolecular cyclization reaction in an automated one‐pot procedure directly from [11C]CO2, thereby precluding the use of [11C]COCl2. Formulated [11C]SL25.1188 was isolated in 12 ± 1% uncorrected radiochemical yield, based on starting [11C]CO2, with a specific activity of 37 ± 2 GBq/µmol at the end of synthesis (30 min; n= 3). Radiochemical and enantiomeric purities were both >99%. The methodology described herein offers an efficient production of [11C]SL25.1188 at ambient temperature and is suitable for human imaging studies.

The performance of small animal photonic imaging has been considerably improved since the development of fluorescence diffuse optical tomography (fDOT), which can reconstruct fluorescent probe distribution inside tissue. However, the quantification capabilities of this new technology are still a topic of debate, especially in comparison to classical nuclear imaging techniques. Here, we present a method to in vivo calibrate the quantity and localization of a probe provided by free-space fDOT (where no plate is compressing the mouse) with positron emission tomography (PET) and x-ray computed tomography, respectively. This methodology allowed us to demonstrate a strong linear correlation (R^2=0.95) between fDOT and PET for probe concentrations ranging from 3nM to 1μM in a deep-seated organ.

The inhibition of cerebral monoamine oxidases (MAOs) by cigarette smoke components could participate to the tobacco addiction. However, the actual extent of this inhibition in vivo in smokers is still poorly known. We investigated cerebral MAO-A availability in 7 tobacco-dependent subjects and 6 healthy nonsmokers, using positron emission tomography (PET) and the MAO-A selective radioligand 11Cbefloxatone. In comparison to nonsmokers, smokers showed a significant overall reduction of 11Cbefloxatone binding potential (BP) in cortical areas (average reduction, −60%) and a similar trend in caudate and thalamus (−40%). Our findings confirm a widespread inhibition of cerebral MAO-A in smokers. This mechanism may contribute to tobacco addiction and for a possible mood-modulating effect of tobacco.