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The nitroaldol reaction of nitro[11C]methane and formaldehyde, which yields 2-(hydroxymethyl)-2-nitro[2-11C]propane-1,3-diol, is explored. The fluoride-ion-assisted nitroaldol reaction using (C4H9)4NF was rapid and provided the desired nitrotriol in more than 97% radiochemical conversion (decay-corrected) in 3 min at room temperature. Neither 2-nitro[2-11C]ethanol nor 2-nitro[2-11C]propane-1,3-diol was observed under the reaction conditions. The preparation of 2-amino-2-(hydroxymethyl)-[2-11C]propane-1,3-diol ([11C]Tris) was described, which was followed by the nitro-group reduction using NiCl2 and NaBH4 in aqueous MeOH. The decay-corrected radiochemical conversion to [11C]Tris was 68.0±6.5% in two steps. Copyright © 2010 John Wiley & Sons, Ltd.

The aim of this study was to evaluate N-benzyl-N-[11C]methyl-2-(7-methyl-8-oxo-2-phenyl-7,8-dihydro-9H-purin-9-yl)acetamide ([11C]DAC) as a new translocator protein (18 kDa) [TSPO, formerly known as the peripheral-type benzodiazepine receptor (PBR)] positron emission tomography (PET) ligand in normal mice and unilateral kainic acid (KA)-lesioned rats. DAC is a derivative of AC-5216, which is a potent and selective PET ligand for the clinical investigation of TSPO. The binding affinity and selectivity of DAC for TSPO were similar to those of AC-5216, and DAC was less lipophilic than AC-5216. The distribution pattern of [11C]DAC was in agreement with TSPO distribution in rodents. No radioactive metabolite of [11C]DAC was found in the mouse brain, although it was metabolized rapidly in mouse plasma. Using small-animal PET, we examined the in vivo binding of [11C]DAC for TSPO in KA-lesioned rats. [11C]DAC and [11C]AC-5216 exhibited similar brain uptake in the lesioned and nonlesioned striatum, respectively. The binding of [11C]DAC to TSPO was increased significantly in the lesioned striatum, and [11C]DAC showed good contrast between the lesioned and nonlesioned striatum (the maximum ratio was about threefold). In displacement experiments, the uptake of [11C]DAC in the lesioned striatum was eventually blocked using an excess of either unlabeled DAC or PK11195 injected. [11C]DAC had high in vivo specific binding to TSPO in the injured rat brain. Therefore, [11C]DAC is a useful PET ligand for TSPO imaging, and its specific binding to TSPO is suitable as a new biomarker for brain injury. Synapse 63:961–971, 2009. © 2009 Wiley-Liss, Inc.

(R)-(−)-2-[11C]Methoxy-N-n-propylnorapomorphine ([11C]MNPA ([11C]2)) is an agonist radioligand of interest for imaging D2/D3 receptors in vivo. Here we sought to develop an improved radiosynthesis of this radioligand. Reference 2 was synthesized in nine steps with an overall yield of about 5%, starting from codeine. Trimethylsilyldiazomethane proved to be a practical improvement in comparison to diazomethane in the penultimate methylation step. A protected precursor for radiolabeling ((R)-(−)-2-hydroxy-10,11-acetonide-N-n-propylnoraporphine, 4) was prepared from (R)-(−)-2-hydroxy-N-n-propylnorapomorphine (1) in 30% yield. [11C]2 was prepared from 4 via a two-step one-pot radiosynthesis. The first step, methylation of 4 with [11C]methyl triflate, occurred in quantitative radiochemical yield. The second step, deprotection of the catechol moiety with HCl and heat, yielded 60–90% of [11C]2 giving an overall incorporation yield from [11C]methyl triflate of 60–90%. In a typical run more than 1 GBq of [11C]2, was produced from carbon-11 generated from a 10-min proton irradiation (16 MeV; 35 µA) of nitrogen–hydrogen target gas. The radiochemical purity of [11C]2 was > 99% and specific radioactivity at the time of injection was 901±342 GBq/µmol (n=10). The total synthesis time was 35–38 min from the end of radionuclide production. The identity of [11C]2 was confirmed by comparing its LC-MS/MS spectrum with those of reference 2 and (R)-(−)-10-methoxy-2,11-dihydroxy-N-n-propylnoraporphine. Copyright © 2009 John Wiley & Sons, Ltd.

The aim of this study was to develop a practical labeling method of [13N]ligands using no-carrier-added [13N]NH3 with high specific activity. [13N]urea analogues [13N]1a and [13N]2a or [13N]carbamate [13N]3a were synthesized by reacting isocyanate 5a, carbamoyl chloride 6a or chloroformate 7a with [13N]NH3. The precursors 5a–7a were prepared by treating amines 8a and 9a and alcohol 10a with triphosgene in situ. These reaction mixtures were not purified and were used directly for [13N]ammonolysis, respectively. Using the one-pot method, we synthesized [13N]carbamazepine ([13N]4), a putative positron emission tomography ligand for brain imaging. Copyright © 2009 John Wiley & Sons, Ltd.

Peripheral benzodiazepine receptor (PBR) is expressed in most organs and its expression is reported to be increased in activated microglia in the brain. [(11)C]PK11195 has been widely used for the in vivo imaging of PBRs, but its signal in the brain was not high enough for stable quantitative analysis. We synthesized a novel positron emission tomography (PET) ligand, [(11)C]DAA1106, for PBR and investigated its in vivo properties in rat and monkey brain. High uptake of [(11)C]DAA1106 was observed in the olfactory bulb and choroid plexus area, followed by the pons/medulla and cerebellum by in vivo autoradiography of rat brain, correlating with the binding in vitro. [(11)C]DAA1106 binding was increased in the dorsal hippocampus with neural destruction, suggesting glial reaction. [(11)C]DAA1106 binding was both inhibited and displaced by 1.0 mg/kg of DAA1106 and 5 mg/kg of PK11195 by 80% and 70%, respectively. Specific binding was estimated as 80% of total binding. [(11)C]DAA1106 binding was four times higher compared to the binding of [(11)C]PK11195 in the monkey occipital cortex. These results indicated that [(11)C]DAA1106 might be a good ligand for in vivo imaging of PBR.

DR4446 (1-methyl-2a-[4-(4,5,6,7-tetrahydrothieno[3,2-c]pyridin-5-yl)butyl]-2a,3,4,5-tetrahydro-1H-benz[cd]indole-2-one) is a potent 5-HT7 receptor antagonist (Ki=9.7 nM) with a high selectivity over other 5-HT family receptors (Ki for 5-HT1A: 770 nM; for other 5-HT receptors: >1000 nM). As a positron emission tomography (PET) tracer for the 5-HT7 receptor, [11C]DR4446 was synthesized at high radiochemical purity ( >98%) with specific activity of 73–120 GBq/μmol at the end of synthesis by the alkylation of the desmethyl precursor (1) with [11C]CH3I in the presence of NaH. A PET study in monkey demonstrated that [11C]DR4446 had good permeability into the brain, and had a specific binding component in the brain regions including the thalamus, possibly an area in the 5-HT7 receptors. Metabolite analysis showed that [11C]DR4446 was relatively stable and low percentages of two radio-labeled metabolites were detected in the plasma of monkey using HPLC. Copyright © 2002 John Wiley & Sons, Ltd.

[Carbonyl-11C]WAY-100635 has been reported to be a useful ligand for the investigation of 5-HT1A receptor imaging in vivo. However, the cellular distribution and the influence of endogenous serotonin (5-HT) on in vivo binding have not been fully examined. In this study, we investigated the effect of 5,7-dihydroxytryptamine-produced destruction of 5-HT neurons, reserpine-induced 5-HT depletion, and fenfluramine-induced 5-HT increase on [carbonyl-11C]WAY-100635 binding in vivo. There was no significant change in the uptake of [carbonyl-11C]WAY-100635 in the slice of 5-HT denervated rat brain except in the raphe nucleus, where 5-HT cell bodies exist. There was no obvious effect of enhanced 5-HT release by fenfluramine or decreased release by reserpine on [carbonyl-11C]WAY-100635 binding in the dissected brain region. No significant effect was observed in the time course of [carbonyl-11C]WAY-100635 in the hippocampus and frontal cortex measured by PET. These results indicated that the in vivo binding of [carbonyl-11C]WAY-100635 in the hippocampus and cerebral cortex mainly reflects postsynaptic 5-HT1A receptor binding, and that this binding is not sensitive to endogenous 5-HT. Synapse 40:122–129, 2001. © 2001 Wiley-Liss, Inc.

Derivatives of 9,10-ethanobenzo[b]quinolizinium are potent antagonists for the TCP-site of the NMDA receptor. Two fluoroethyl-substituted analogues were labelled with fluorine-18 by displacement of the tosylate with [18F]fluoride, followed by a Diels-Alder reaction. A methoxy-substituted analogue labelled with carbon-11 was obtained by O-methylation of the corresponding hydroxy precursor with [11C]iodomethane. In biodistribution studies in mice with these three radioligands, it was found that they have little ability to penetrate the blood-–brain barrier. Copyright © 2000 John Wiley & Sons, Ltd.

Two phencyclidine (PCP) analogs, 3 and 4, and one thienylcyclohexyl-piperidine (TCP) analog, (±)6, were labeled with positron emitter carbon-11. These compounds displayed higher in vitro binding affinities than PCP itself for the PCP-binding site located inside the ion channel on the N-methyl-D-aspartate (NMDA) receptors. Brain distribution studies in mice showed different uptake characteristics between the PCP and TCP analogs, indicating their different in vivo interactions with the brain components including the PCP-binding site probably due to the different physicochemical properties of the molecules. © 1998 John Wiley & Sons, Ltd.

In previous studies, we have found that [11C]L-703,717, a positron-emitter labeled antagonist for the glycine-binding site of NMDA receptors, only localizes in rodent cerebellum under in vivo conditions. In order to understand the unusual cerebellar localization, we have examined the binding of [11C]L-703,717 to a cerebellar-specific NMDA receptor subtype consisting of GLuRϵ3 subunit, by comparing its autoradiographic distributions between GluRϵ3-deficient and wild-type mice. Ex vivo [11C]L-703,717 binding to wild-type mice showed a highly specific localization of radioactivity in the cerebellum, whereas that to the GluRϵ3-deficient mice showed no specific localization of radioactivity in any of the brain regions. In contrast to the ex vivo binding, in vitro [11C]L-703,717 binding displayed a similar binding characteristic between GluRϵ3-deficient and wild-type mice with highly specific localizations in the hippocampus and cerebral cortex. Therefore, the present study clearly demonstrated that [11C]L-703,717 preferentially binds to a cerebellar NMDA receptor subtype consisting of GluRϵ3 subunit in vivo, but not in vitro. Synapse 43:131–133, 2002. © 2001 Wiley-Liss, Inc.

A new derivative of 4,5,9,10-tetrahydro-1,4-ethanobenz[b]quinolizine (2) has been designed as a prodrug for its quinolizinium cation (1) that is a potent antagonist of the TCP-binding site of NMDA receptors at the open state. The 11C-labeled 2 showed high accumulation of radioactivity in the brain in an in vivo biodistribution study. The speculation of 2 as a prodrug of 1 has been proven by the fact that 1 was observed in a high ratio to 2 in an analysis by RP-HPLC of the brain homogenates.

Recent studies revealed that thalidomide (1) has unique and broad pharmacological effects on multi-targets although the application of 1 in therapy is still controversial. In this study, we synthesized nitrogen-13-labeled thalidomide ([13N]1) as a potential positron emission tomography (PET) probe using no-carrier-added [13N]NH3 as a labeling agent. By use of an automated system, [13N]1 was prepared by reacting N-phthaloylglutamic anhydride (2) with [13N]NH3, following by cyclization with carbonyldiimidazole in a radiochemical yield of 56±12% (based on [11N]NH3, corrected for decay) and specific activity of 49±24 GBq/µmol at the end of synthesis (EOS). At EOS, 570–780 MBq (n=7) of [13N]1 was obtained at a beam current of 15 µA after 15 min proton bombardment with a synthesis time of 14 min from the end of bombardment. Using a small animal PET scanner, preliminary biodistribution of [13N]1 in mice was examined. Copyright © 2010 John Wiley & Sons, Ltd.

In this study, we report the synthesis and reactivity of [ 18 F]fluoromethyl iodide ([ 18 F]FCH 2 I) with various nucleophilic substrates and the stabilities of [ 18 F]fluoromethylated compounds. [ 18 F]FCH 2 I was prepared by reacting diiodomethane (CH 2 I 2 ) with [ 18 F]KF, and purified by distillation in radiochemical yields of 14–31% ( n = 25). [ 18 F]FCH 2 I was stable in organic solvents commonly used for labeling and aqueous solution with pH 1–7, but was unstable in basic solutions. [ 18 F]FCH 2 I displayed a high reactivity with various nucleophilic substrates such as phenol, thiophenol, amide and amine. The [ 18 F]fluoromethylated compounds synthesized by the reactions of phenol, thiophenol and tertiary amine with [ 18 F]FCH 2 I were stable for purification, formulation and storage. In contrast, the [ 18 F]fluoromethylated compounds synthesized by the reactions of primary or secondary amines, and amide with [ 18 F]FCH 2 I were too unstable to be detected or purified from the reaction mixtures. Defluorination of these [ 18 F]fluoromethyl compounds was a main decomposition route.

The potentiometric titration curves of carboxymethylcellulose, which has a relatively stiff backbone, and also of poly(D-glutamic acid) in the helical region are compared with the theoretical curves calculated assuming that the polyions are rods and have smeared charges on their surfaces. For carboxymethylcellulose good agreement is observed when its charge density is high, whereas as the charge density decreases the calculated curves deviate from the observed ones. The main reason for the disagreement at low charge densities may be attributed to the flexibility of the polymer backbone. For helical poly(D-glutamic acid) satisfactory agreement between calculated and observed curves is found if a radius thicker than the realistic radius is employed. The reason for the excessively large radius may be attributed to the inapplicability of the smeared charge model.