Synthesis of deuterium and 15N‐labelled 2,5‐Bis[5‐amidino‐2‐pyridyl]furan and 2,5‐Bis[5‐(methoxyamidino)‐2‐pyridyl]furan

The acetate salt of 2,5‐bis[5‐amidino‐2‐pyridyl]furan‐d₂/¹⁵N₂ ( 4) was synthesized from 2,5‐bis[5‐cyano‐2‐pyridyl]furan‐d₂ ( 2 ), through the bis‐O‐acetoxyamidoxime followed by hydrogenation. Compound 2 was obtained via a Stille coupling reaction of 6‐chloronicotinonitrile with 2,5‐bis[tri‐n‐butyltin]‐furan‐d₂ ( 1 ). 2,5‐bis[5‐amidino‐2‐pyridyl)furan‐d₆ ( 10) was synthesized from 2,5‐bis[5‐cyano‐2‐pyridyl)furan‐d₆ ( 9 ) via a direct reaction with lithium bis(trimethylsilyl)amide, followed by deprotection with ethanolic HCl. ¹⁵N and/or deuterium‐labelled methoxy‐amidines 5a ‐d₂/¹⁵N₂, 5b ‐d₈, 12 , 14 ‐d₆ were prepared in good yield via direct methylation of their respective diamidoximes with either dimethylsulfate‐d₀ or dimethylsulfate‐d₆ in DMF solution and using LiOH as a base. Copyright © 2006 John Wiley & Sons, Ltd.     

Synthesis of C‐14 and C‐13, H‐2‐labeled IKK inhibitor: [14C] and [13C4,D3]‐N‐(6‐chloro‐7‐methoxy‐9H‐pyrido[3,4‐b]indol‐8‐yl)‐2‐methyl‐3‐pyridinecarboxamide

[¹⁴C]‐N‐(6‐Chloro‐7‐methoxy‐9H‐pyrido [3,4‐b]indol‐8‐yl)‐2‐methyl‐3‐pyridinecarboxamide (5B ), an IKK inhibitor, was synthesized from [¹⁴C]‐barium carbonate in two steps in an overall radiochemical yield of 41%. The intermediate, [carboxyl‐¹⁴C]‐2‐methylnicotinic acid, was prepared by the lithiation and carbonation of 3‐bromo‐2‐methylpyridine. [¹³C₄,D₃]‐N‐(6‐chloro‐7‐methoxy‐9H‐pyrido [3,4‐b]indol‐8‐yl)‐2‐methyl‐3‐pyridinecarboxamide (5C ) was synthesized from [1,2,3,4‐¹³C₄]‐ethyl acetoacetate and [D₄]‐methanol in six steps in an overall yield of 2%. [¹³C₄]‐2‐methylnicotic acid, was prepared by condensation of [¹³C₄]‐ethyl 3‐aminocrotonate and acrolein, followed by hydrolysis with lithium hydroxide. Copyright © 2006 John Wiley & Sons, Ltd.     

Radiosynthesis of N‐[4‐(4‐fluorobenzyl)piperidin‐1‐yl]‐N′‐(2‐[11C]oxo‐1,3‐dihydrobenzimidazol‐5‐yl)oxamide,a NR2B‐selective NMDA receptor antagonist

In order to perform in vivo imaging of the NR2B NMDA receptor system by positron emission tomography, a NR2B selective NMDA receptor antagonist has been labelled with carbon‐11 (half‐life: 20 min). N‐[4‐(4‐fluorobenzyl)piperidin‐1‐yl]‐N′‐(2‐oxo‐1,3‐dihydrobenzimidazol‐5‐yl)oxamide has been described demonstrating high affinity and selectivity for the NR2B receptors (IC₅₀ of 5 nM in [³H]Ro‐25,6981 binding assay). The labelling precursor and the reference compound were synthesized by coupling the 4‐(4‐fluorobenzyl)piperidine with the corresponding oxalamic acid. The reaction of [¹¹C]phosgene with phenylenediamine precursor led the formation of the [¹¹C]benzimidazolone ring present on the ligand. The labelling occurred in THF or acetonitrile and the decay corrected radiochemical yield was 30–40% from the produced [¹¹C]methane. 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 GBq/µmol (2–3.4 Ci/µmol) at the end of synthesis. Copyright © 2009 John Wiley & Sons, Ltd.     

Synthesis and preliminary in vivo evaluation of 4‐[18F]fluoro‐N‐{2‐[4‐(6‐trifluoromethylpyridin‐2‐yl)piperazin‐1‐yl]ethyl}benzamide,a potential PET radioligand for the 5‐HT1A receptor

4‐Fluoro‐N‐{2‐[4‐(6‐trifluoromethylpyridin‐2‐yl)piperazin‐1‐yl]ethyl}benzamide is a full 5‐HT_1A agonist with high affinity (pK_i=9.3), selectivity and a c log P of 3.045. The corresponding PET radioligand 4‐[¹⁸F]fluoro‐N‐{2‐[4‐(6‐trifluoromethylpyridin‐2‐yl)piperazin‐1‐yl]ethyl}benzamide was synthesized by nucleophilic aromatic substitution on the nitro precursor. The fluorinating agent K[¹⁸F]F/Kryptofix 2.2.2 was both dried (9 min, 700 W) and incorporated in the precursor (5 min, 700 W) using a commercially available microwave oven. In a total synthesis time of 60 min, an overall radiochemical yield of 18% (SD=5, n=7, EOS) was obtained. Radiochemical purity was always higher than 99% and specific activity always higher than 81.4 GBq/µmol (2.2 Ci/µmol). Initial brain uptake in mice was 2.19% ID (5.47% ID/g, 2 min) but decreased rapidly (0.17% ID, 0.45% ID/g (60 min)). During the first 20 min p.i., radioactivity concentration of the brain was significantly higher than that of blood demonstrating good brain entry of the tracer. Copyright © 2004 John Wiley & Sons, Ltd.     

Synthesis of 6‐chloro‐3‐((2‐(S)‐azetidinyl)methoxy)‐5‐(2‐[18F]fluoropyridin‐4‐yl)pyridine ([18F]NIDA 522131), a novel potential radioligand for studying extrathalamic nicotinic acetylcholine receptors by PET

6‐Chloro‐3‐((2‐(S)‐azetidinyl)methoxy)‐5‐(2‐[¹⁸F]fluoropyridin‐4‐yl)pyridine ([¹⁸F]NIDA 522131), a potential radioligand for studying extrathalamic nicotinic acetylcholine receptors by positron‐emission tomography, was synthesized via no‐carrier‐added nucleophilic [¹⁸F]fluorination of 6‐chloro‐3‐((1‐(tert‐butoxycarbonyl)‐2‐(S)‐azetidinyl)methoxy)‐5‐(2‐iodopyridin‐4‐yl)vinyl)pyridine, followed by acidic deprotection. The overall radiochemical yield of the radiosynthesis was 4–8% (non‐decay‐corrected), the specific radioactivity was in the range of 167–335 GBq/µmol (4500–9000 mCi/µmol) and the radiochemical purity was greater than 99%. Preparation of [¹⁸F]NIDA522131 via corresponding bromo‐derivative 2 is also described. Copyright © 2004 John Wiley & Sons, Ltd.     

Synthesis and Positive Inotropic Evaluation of (E)‐2‐(4‐Cinnamylpiperazin‐1‐yl)‐N‐(1‐substituted‐4,5‐dihydro‐[1,2,4]triazolo[4,3‐a]quinolin‐7‐yl)acetamides

A series of (E)‐2‐(4‐cinnamylpiperazin‐1‐yl)‐N‐(1‐substituted‐4,5‐dihydro‐[1,2,4]triazolo[4,3‐a]quinolin‐7‐yl)acetamides were synthesized and evaluated for their positive inotropic activity by measuring the left atrium stroke volume on isolated rabbit heart preparations. This class of compounds presented favorable in vitro activity compared with the standard drug, milrinone, among which N‐(1‐(3‐chlorophenyl)‐4,5‐dihydro‐[1,2,4]triazolo[4,3‐a]quinolin‐7‐yl)‐2‐(4‐cinnamylpiperazin‐1‐yl)acetamide 5e was found to be the most potent with 16.58 ± 0.11% increased stroke volume (milrinone: 2.46 ± 0.07%) at a concentration of 3 × 10^?5 M. The chronotropic effects of the compounds having inotropic effects were also evaluated.     

Efficient synthesis of 6‐chloro‐3‐((2‐(S)‐azetidinyl)methoxy)‐5‐((E)‐2‐(2‐[18F]fluoropyridin‐4‐yl)vinyl)pyridine ([18F]NIDA 52289), a very high affinity radioligand for nicotinic acetylcholine receptors

6‐Chloro‐3‐((2‐(S)‐azetidinyl)methoxy)‐5‐((E)‐2‐(2‐[¹⁸F]fluoropyridin‐4‐yl)vinyl)pyridine ([¹⁸F]NIDA 52289), a very high affinity radioligand for studying nicotinic acetylcholine receptors (nAChRs) by positron‐emission tomography, was synthesized through Kryptofix 222 assisted no‐carrier‐added nucleophilic [¹⁸F]fluorination of 6‐chloro‐3‐((1‐(tert‐butoxycarbonyl)‐2‐(S)‐azetidinyl)methoxy)‐5‐((E)‐2‐(2‐bromopyridin‐4‐yl)vinyl)pyridine, followed by acidic deprotection. The overall radiochemical yield of the radiosynthesis was 10% (non‐decay‐corrected), the specific radioactivity was in the range of 93–326 GBq/µmol (2.5–8.8 mCi/µmol) and the radiochemical purity was greater than 99%. Copyright © 2004 John Wiley & Sons, Ltd.     

Synthesis of carbon‐14‐labeled isotopomer of 6‐(4‐methanesulfonylphenyl)‐5‐[4‐(2‐piperidin‐1‐yl‐ethoxy)phenoxy]‐naphthalen‐2‐ol HCL salt (LY2066948‐[14C] HCL salt)

Carbon‐14‐labeled 6‐(4‐methanesulfonylphenyl)‐5‐[4‐(2‐piperidin‐1‐yl‐ethoxy)phenoxy]naphthalen‐2‐ol, a novel selective estrogen receptor modulator (SERM) was synthesized. The key component, 6‐methoxy‐1‐tetralone‐[carbonyl‐¹⁴C], was synthesized from 3‐(3‐methoxyphenyl)‐propionic acid via an intra‐molecular Friedel–Crafts acylation of 4‐(3‐methoxyphenyl)butanoic acid‐[carboxy‐¹⁴C]. A palladium catalyzed alpha‐keto arylation of 6‐methoxy‐1‐tetralone with 4‐methanesulfonyl‐phenyl bromide, followed by a sequence of bromination, DDQ dehydrogenation, aryl Ullmann reaction, and demethylation with BBr₃ gave the desired product LY2066948‐[¹⁴C]. Copyright © 2007 John Wiley & Sons, Ltd.     

Synthesis and in vivo evaluation of [O‐methyl‐11C] 2‐(4‐methoxyphenyl)‐N‐(4‐methylbenzyl)‐N‐(1‐methyl‐ piperidin‐4‐yl)acetamide as an imaging probe for 5‐HT2A receptors

2‐(4‐Methoxyphenyl)‐N‐(4‐methylbenzyl)‐N‐(1‐methylpiperidin‐4‐yl)acetamide (AC90179, 4 ), a highly potent and selective competitive 5‐HT_2A antagonist, was labeled by [¹¹C]‐methylation of the corresponding desmethyl analogue 5 with [¹¹C]methyl triflate. The precursor molecule 5 for radiolabeling was synthesized from p‐tolylmethylamine in three steps with 46% overall yield. [¹¹C]AC90179 was synthesized in 30 min (30 ± 5% yield, EOS) with a specific activity of 4500 ± 500 Ci/mmol and >99% chemical and radiochemical purities. Positron emission tomography studies in anesthetized baboon revealed that [¹¹C] 4 Penetrates the blood–brain barrier (BBB) with a rapid influx and efflux of the tracer in all brain regions. Due to lack of tracer retention or specific binding, [¹¹C] 4 cannot be used as PET ligand for imaging 5‐HT_2A receptors. Copyright © 2006 John Wiley & Sons, Ltd.     

Synthesis and Positive Inotropic Evaluation of 2‐(4‐(4‐Substituted benzyloxy)‐3‐methoxybenzyl)‐1,4‐diazepan‐1‐yl)‐N‐(4,5‐dihydro‐1‐methyl[1,2,4]triazolo[4,3‐a]quinolin‐7‐yl)‐acetamides

In an attempt to search for more potent positive inotropic agents, a series of 2‐(4‐(4‐substituted benzyloxy)‐3‐methoxybenzyl)‐1,4‐diazepan‐1‐yl)‐N‐(4,5‐dihydro‐1‐methyl[1,2,4]triazolo[4,3‐a]quinolin‐7‐yl)acetamides was synthesized and their positive inotropic activities were evaluated by measuring left atrium stroke volume on isolated rabbit‐heart preparations. Several compounds showed favorable activity compared with the standard drug Milrinone among which 2‐(4‐(4‐(2‐chlorobenzyloxy)‐3‐methoxybenzyl)‐1,4‐diazepan‐1‐yl)‐N‐(4,5‐dihydro‐1‐methyl‐[1,2,4]triazolo[4,3‐a]quinolin‐7‐yl)acetamide 6e was found to have the most desirable potency with the 6.79 ± 0.18% increased stroke volume (Milrinone: 1.67 ± 0.64%) at a concentration of 1×10^–5 M in our in‐vitro study. The chronotropic effects of those compounds having inotropic effects were also evaluated in this work.     

Synthesis of N‐(piperidin‐1‐yl)‐5‐(4‐methoxyphenyl)‐1‐(2‐chlorophenyl)‐4‐[18F]fluoro‐1H‐pyrazole‐3‐carboxamide by nucleophilic [18F] fluorination: a PET radiotracer for studying CB1 cannabinoid receptors

The feasibility of nucleophilic displacement of bromide in the 4‐bromopyrazole ring with [¹⁸F]fluoride has been demonstrated by the synthesis of two radiolabeled compounds: N‐(piperidin‐1‐yl)‐5‐(4‐methoxyphenyl)‐1‐(2‐chlorophenyl)‐4‐[¹⁸F]fluoro‐1H‐pyrazole‐3‐carboxamide, ([¹⁸F] NIDA‐42033) 1b and 1‐(2‐chlorophenyl)‐4‐[¹⁸F]fluoro‐5‐(4‐methoxyphenyl)‐1H‐pyrazole‐3‐carboxylic acid, ethyl ester 4 . The radiochemical yields were in the range of 1–6%. [¹⁸F]NIDA‐42033, a potential radiotracer for the study of CB₁ cannabinoid receptors in the animal brain by positron emission tomography, has been synthesized in sufficient quantities with specific radioactivity greater than 2500 mCi/μmol and radiochemical purity >95%. Copyright © 2002 John Wiley & Sons, Ltd.     

Synthesis of [3H]‐labelled 4‐[Ethyl[2,5,6‐trimethyl‐7‐(2,4,6‐trimethylphenyl)pyrrolo[2,3‐d]pyrimidin‐4‐yl]amino]‐2,3‐[3H]‐butan‐1‐ol: a high affinity radioligand for the corticotropin‐releasing hormone type 1 receptor

[³H]‐Labelled 4‐[ethyl[2,5,6‐trimethyl‐7‐(2,4,6‐trimethylphenyl)pyrrolo[2,3‐d]pyrimidin‐4‐yl]amino]‐2,3‐[³H]‐butan‐1‐ol ( 3b ) was prepared as a novel non‐peptidic radiolabelled high affinity antagonist of the corticotropin‐releasing hormone type 1 receptor (CRHR₁) that could be useful as a more stable and receptor‐selective alternative to the radiolabelled peptides now used to label the CRHR₁ receptor for displacement studies in cell‐based binding assays. The precursor (Z)‐4‐[ethyl[2,5,6‐trimethyl‐7‐(2,4,6‐trimethylphenyl)pyrrolo[2,3‐d]pyrimidin‐4‐yl]amino]but‐2‐en‐1‐ol ( 2 ) was reduced with tritium gas using palladium as the catalyst. After HPLC purification 3b was obtained with a specific activity of 35 Ci/mmol in high radiochemical purity (>97%). Copyright © 2006 John Wiley & Sons, Ltd.     

Radiosynthesis of microtubule‐targeted theranostic methyl N‐[5‐(3’‐radiohalobenzoyl)‐1H‐benzimidazol‐2‐yl]carbamates

Microtubules are a target for a broad spectrum of drugs used as chemotherapeutics to treat hematological malignancies and solid tumors. Most of these drugs have significant dose‐limiting toxicities including peripheral neuropathies that can be debilitating and permanent. In an ongoing effort to develop safer and more effective drugs, benzimidazole‐based compounds are being developed as replacement for vincristine and similar agents. In this report, we describe radiosyntheses of novel microtubule‐targeting methyl N‐[5‐(3’‐radiohalobenzoyl)‐1H‐benzimidazol‐2‐yl]carbamates 4 that are intended as potential imaging agents and molecular radiotherapeutics. ¹²⁵I‐ and ¹³¹I‐radiolabeled derivatives were prepared either by direct radioiodination of methyl N‐(6‐benzoyl‐1H‐benzimidazol‐2‐yl)carbamate 1 or radioiododestannylation of the corresponding stannane precursor 3 . The direct radioiodination was conducted in a solution of 1 in triflic acid and produced after ~1 hour at elevated temperatures and HPLC purification on average 62% of the no‐carrier added products ¹²⁵I‐ 4 and ¹³¹I‐ 4 . Radioiododestannylation of 3’‐trimethylstannane 3 proceeded with ease at room temperature in the presence of H₂O₂ as the oxidant and produced no‐carrier‐added ¹²⁵I‐ 4 and ¹³¹I‐ 4 in high isolated yields, on average 85%. The radiohalodestannylation protocol is universal and can be applied to other radiohalides including ¹²⁴I to produce ¹²⁴I‐ 4 , a positron emission tomography agent, and ²¹¹At to produce ²¹¹At‐ 4 , an α‐particle emitting radiotherapeutic.     

New pyrazole derivative 5‐[1‐(4‐fluorophenyl)‐1H‐pyrazol‐4‐yl]‐2H‐tetrazole: synthesis and assessment of some biological activities

The molecular modification and synthesis of compounds is vital to discovering drugs with desirable pharmacological and toxicity profiles. In response to pyrazole compounds' antipyretic, analgesic, and anti‐inflammatory effects, this study sought to evaluate the analgesic, anti‐inflammatory, and vasorelaxant effects, as well as the mechanisms of action, of a new pyrazole derivative, 5‐[1‐(4‐fluorophenyl)‐1H‐pyrazol‐4‐yl]‐2H‐tetrazole. During the acetic acid‐induced abdominal writhing test, treatments with 5‐[1‐(4‐fluorophenyl)‐1H‐pyrazol‐4‐yl]‐2H‐tetrazole reduced abdominal writhing, while during the formalin test, 5‐[1‐(4‐fluorophenyl)‐1H‐pyrazol‐4‐yl]‐2H‐tetrazole reduced licking times in response to both neurogenic pain and inflammatory pain, all without demonstrating any antinociceptive effects, as revealed during the tail flick test. 5‐[1‐(4‐fluorophenyl)‐1H‐pyrazol‐4‐yl]‐2H‐tetrazole also reduced carrageenan‐induced paw edema and cell migration during the carrageenan‐induced pleurisy test. As demonstrated by the model of the isolated organ, 5‐[1‐(4‐fluorophenyl)‐1H‐pyrazol‐4‐yl]‐2H‐tetrazole exhibits a vasorelaxant effect attenuated by Nω‐nitro‐l ‐arginine methyl ester, 1H‐[1,2,4]oxadiazolo[4,3‐alpha]quinoxalin‐1‐one, tetraethylammonium or glibenclamide. 5‐[1‐(4‐fluorophenyl)‐1H‐pyrazol‐4‐yl]‐2H‐tetrazole also blocked CaCl₂‐induced contraction in a dose‐dependent manner. Suggesting a safe toxicity profile, 5‐[1‐(4‐fluorophenyl)‐1H‐pyrazol‐4‐yl]‐2H‐tetrazole reduced the viability of 3T3 cells at higher concentrations and was orally tolerated, despite signs of toxicity in doses of 2000 mg/kg. Lastly, the compounds' analgesic activity might be attributed to the involvement of the NO/cGMP pathway and K⁺ channels observed in the vasorelaxant effect.     

N‐[3‐[4‐(2‐methoxyphenyl) piperaziny‐1‐yl]propyl]cyclam: synthesized as a potential 5‐HT1A receptor ligand and labelled with 99mTc‐nitrido core

This paper reports the synthesis of new potential 5‐HT_1A receptor ligand N‐[3‐[4‐(2‐methoxyphenyl)piperaziny‐1‐yl]propyl]cyclam (MPPC) and radiolabelling of it with ^99mTc‐nitrido core. The novel neutral complex ^99mTcN‐MPPC combines 1,4,8,11‐tetraazacyclotetradecane (cyclam) ligand as chelate moiety for ^99mTc‐nitrido with a 1‐(2‐methoxyphenyl)piperazine moiety derived from WAY 100635 via a 3‐carbon alkyl chain. This provided a reliable and reproducible method for attaching the technetium to the pharmacophore moiety of WAY 100635. ^99mTcN‐MPPC was prepared by a two‐step procedure and the radiochemical purity was found to be greater than 95%. It was hydrophilic and stable for at least 4 h at room temperature. In vivo stability study in normal rats showed that no degradation of ^99mTcN‐MPPC was found in deproteinated blood samples at 2 h post‐injection. This effective ^99mTc‐labelling strategy for obtaining neutral ^99mTc nitrido complexes would be a useful tool to prepare new SPECT agents to image 5‐HT_1A receptor with cyclam conjugated ligands. Copyright © 2008 John Wiley & Sons, Ltd.     

N‐2‐(4‐N‐(4‐[18F]Fluorobenzamido)phenyl)‐propyl‐2‐propanesulphonamide: synthesis and radiofluorination of a putative AMPA receptor ligand

Arylpropylsulphonamides are in the focus of research as α‐amino‐3‐hydroxy‐5‐methyl‐4‐isoxazolpropionic acid (AMPA) receptor ligands. A new fluorine‐18‐labelled potentiator of AMPA receptors was synthesized as a potential radiotracer for cerebral imaging with positron emission tomography. Using N‐2‐(4‐N‐(4‐nitrobenzamido)phenyl)‐propyl‐2‐propanesulphonamide ( 7 ) as labelling precursor for a Kryptofix 2.2.2^®/K₂CO₃‐activated nucleophilic radiofluorination, the putative AMPA receptor ligand N‐2‐(4‐N‐(4‐[¹⁸F]fluorobenzamido)phenyl)‐propyl‐2‐propanesulphonamide [¹⁸F] 8 was obtained in one step. Optimization of the reaction parameters time, temperature, solvent and concentration gave a radiochemical yield of 38±8% at 180°C in dimethylsulphoxide within 30‐min reaction time. After a solid‐phase extraction followed by a high‐performance liquid chromatography separation, the product could be obtained in radiochemical yields of 5±1.5%. Radiochemical purity was higher than 95% and the specific activity amounted to 77±40 GBq/µmol. First in vitro assays with rat brain slices revealed a high non‐specific binding and a uniform distribution of [¹⁸F] 8 not lending it for in vivo imaging purposes. Copyright © 2007 John Wiley & Sons, Ltd.     

Synthesis,In Vitro Protoporphyrinogen Oxidase Inhibition,and Herbicidal Activity of N‐(Benzothiazol‐5‐yl)hexahydro‐1H‐isoindole‐1,3‐diones and N‐(Benzothiazol‐5‐yl)hexahydro‐1H‐isoindol‐1‐ones

Protoporphyrinogen oxidase ( EC 1.3.3.4 ) is one of the most significant targets for a large family of herbicides. As part of our continuous efforts to search for novel protoporphyrinogen oxidase‐inhibiting herbicides, N‐(benzothiazol‐5‐yl)tetrahydroisoindole‐1,3‐dione was selected as a lead compound for structural optimization, leading to the syntheses of a series of novel N‐(benzothiazol‐5‐yl)hexahydro‐1H‐isoindole‐1,3‐diones ( 1a – o ) and N‐(benzothiazol‐5‐yl)hexahydro‐1H‐isoindol‐1‐ones ( 2a – i ). These newly prepared compounds were characterized by elemental analyses, ¹H NMR, and ESI‐MS, and the structures of 1h and 2h were further confirmed by X‐ray diffraction analyses. The bioassays indicated that some compounds displayed comparable or higher protoporphyrinogen oxidase inhibition activities in comparison with the commercial control. Very promising, compound 2a , ethyl 2‐((6‐fluoro‐5‐(4,5,6,7‐tetrahydro‐1‐oxo‐1H‐isoindol‐2(3H)‐yl)benzo[d]thiazol‐2‐yl)‐sulfanyl)acetate, was recognized as the most potent candidate with K_i value of 0.0091 μm . Further greenhouse screening results demonstrated that some compounds exhibited good herbicidal activity against Chenopodium album at the dosage of 150 g/ha.     

Radiosynthesis of 3‐(3‐[18F]fluoropropoxy)‐4‐(benzyloxy)‐N‐[(1‐dimethylaminocyclopentyl)methyl]‐5‐methoxybenzamide,a potential PET radiotracer for the glycine transporter GlyT‐2

The recently described selective and potent GlyT2 antagonist, 4‐benzyloxy‐3,5‐dimethoxy‐N‐[(1‐dimethylaminocyclopentyl) methyl]benzamide (IC₅₀=16 nM) provided an important additional tool to further characterize GlyT2 pharmacology. In order to identify an effective PET radioligand for in vivo assessment of the GlyT‐2 transporter, 3‐(3‐[¹⁸F]fluoropropoxy)‐4‐(benzyloxy)‐N‐((1‐dimethylaminocyclopentyl) methyl)‐5‐methoxybenzamide ([¹⁸F] 3 ), a novel analog of 4‐benzyloxy‐3,5‐dimethoxy‐N‐[(1‐dimethylaminocyclopentyl) methyl]benzamide was synthesized using a one‐pot, two‐step method. The NCA radiofluorination of 1,3‐propanediol di‐p‐tosylate in the presence of K₂CO₃ and Kryptofix‐222 in acetonitrile gave 81% 3‐[¹⁸F]fluoropropyl tosylate, which was subsequently coupled with 4‐benzyloxy‐3‐hydroxy‐5‐methoxy‐N‐[(1‐dimethylaminocyclopentyl) methyl]benzamide in the same reaction vessel. Solvent extraction and HPLC (Eclipse XDB‐C8 column, 80/20/0.1 MeOH/H₂O/Et₃N, 3.0 ml/min) gave [¹⁸F] 3 in 98.5% radiochemical purity. The radiochemical yield was determined to be 14.0–16.2% at EOS, and the specific activity was 1462±342 GBq/µmol. The time of synthesis and purification was 128 min. The final product was prepared as a sterile saline solution suitable for in vivo use. Copyright © 2006 John Wiley & Sons, Ltd.     

A novel method for the synthesis of carbon‐14‐labeled N‐[3‐(1‐methyl‐4‐piperidinyl)‐1H‐pyrrolo[3,2‐b]pyridin‐5‐yl]propanamide and its use in quantitative whole‐body autoradiography studies

Sumitriptan ( 1 ), a non‐selective 5‐HT_1B/1D agonist is an effective therapeutic agent for the acute treatment of migraine, but it is contraindicated for use in patients with known heart disease. The first Selective Serotonin One F Receptor Agonist (SSOFRA), 5‐(4′‐fluorobenz‐amido)‐3‐(N‐methyl‐piperidin‐4‐yl)‐1H‐indole ( 2 ) was demonstrated to be clinically useful in the treatment of migraine. Although 2 exhibited high affinity for the 5‐HT_1F receptor as well as high selectivity for the 5‐HT_1F receptor relative to 5‐HT_1B and 5‐HT_1D receptors, it demonstrated appreciable affinity for the 5‐HT_1A receptor. Subsequently, a program was launched to discover SSOFRA's with improved selectivity over other 5‐HT₁ receptor subtypes. As a result of these efforts, N‐[3‐(1‐methyl‐4‐piperidinyl)‐1H‐pyrrolo[3,2‐b]pyridin‐5‐yl]propanamide ( 3 ) was found to possess greater than 100‐fold selectivity over 5‐HT_1A, 5‐HT_1B and 5‐HT_1D receptors. Pursuant to a potential clinical investigation of 3 , its carbon‐14‐labeled isotopomer has been prepared by a circuitous route from unlabeled 3 and used in quantitative whole‐body autoradiography studies in rats. The results of these efforts are reported herein. Copyright © 2005 John Wiley & Sons, Ltd.     

Radiosynthesis of (S)‐5‐methoxymethyl‐3‐[6‐(4,4,4‐trifluorobutoxy)benzo[d]isoxazol‐3‐yl] oxazolidin‐2‐[11C]one ([11C]SL25.1188), a novel radioligand for imaging monoamine oxidase‐B with PET

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 ED_{50 (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 (T_1/2: 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.