Functional identification of β3‐adrenoceptors in the guinea‐pig ileum using the non‐selective β‐adrenoceptor antagonist (±)‐bupranolol

1 To clarify whether there is a species difference or a tissue difference in β₃‐adrenoceptors, the β₃‐adrenoceptors mediating relaxations to catecholamines ((–)‐isoprenaline, (–)‐noradrenaline and (–)‐adrenaline), a selective β₃‐adrenoceptor agonist BRL37344 and a non‐conventional partial β₃‐adrenoceptor agonist (±)‐CGP12177A (a potent β₁‐ and β₂‐adrenoceptor antagonist with a partial β₃‐adrenoceptor agonist property) were investigated in the guinea‐pig ileum. 2 Catecholamines and β₃‐adrenoceptor agonists induced concentration‐dependent relaxations of pre‐contracted strips of the guinea‐pig ileum. The rank order for their relaxing potency was (–)‐isoprenaline (pD₂: 7.60) > BRL37344 (7.05) > (–)‐noradrenaline (6.38) > (±)‐CGP12177A (6.25) > (–)‐adrenaline (6.07). 3 In the presence of the non‐selective β₁‐ and β₂‐adrenoceptor antagonist (±)‐propranolol (1 μM ), only small rightward shifts of the concentration–response curves (CRCs) to these agonists were observed and the rank order of potency of agonists was BRL37344 (pD₂: 7.00) > (±)‐CGP12177A (6.17) > (–)‐isoprenaline (6.01) > (–)‐noradrenaline (5.69) > (–)‐adrenaline (5.41). 4 In the presence of (±)‐propranolol (1 μM ), the additional presence of (±)‐bupranolol (3–30 μM ), a non‐selective β₁‐, β₂‐ and β₃‐adrenoceptor antagonist, caused a concentration‐dependent rightward shift of the CRCs to catecholamines and β₃‐adrenoceptor agonists. Schild plot analyses of (±)‐bupranolol against these agonists gave pA₂ values of 6.02 ((–)‐isoprenaline), 6.03 ((–)‐noradrenaline), 6.01 ((–)‐adrenaline), 6.56 (BRL37344) and 5.74 ((±)‐CGP12177A), respectively. All Schild plot slopes were not significantly different from unity. The pA₂ values of (±)‐bupranolol obtained for the guinea‐pig β₃‐adrenoceptors were about one log unit less than the values obtained for the rat β₃‐adrenoceptors and about two log units less than the values obtained for dog β₃‐adrenoceptors. 5 These results confirm that functional β₃‐adrenoceptors are present in the guinea‐pig ileum and that the relaxations of these agonists are mainly mediated via β₃‐adrenoceptors in this tissue. The differential antagonistic potency of (±)‐bupranolol may suggest that there is a species difference between the three species (guinea‐pig, dog and rat) in their β₃‐adrenoceptors.     

Synthesis of (±)‐6,6‐[2H6]dimethyl‐11‐nor‐Δ9‐tetrahydrocannabivarin‐9‐carboxylic acid

Starting from divarinol ( 4 ) using previously published procedures, (±)‐6,6‐[²H₆]Dimethyl‐11‐nor‐Δ⁹THCV‐9‐carboxylic acid ( 3 ) was synthesized for use as an internal standard in GC/MS analysis of 11‐nor‐Δ⁹THCV‐9‐carboxylic acid ( 2 ). The detection of 2 distinguishes the use of marijuana from the ingestion of Marinol^®. Copyright © 2002 John Wiley & Sons, Ltd.     

(±)-Govadine and (±)-THP,Two Tetrahydroprotoberberine Alkaloids,as Selective α1-Adrenoceptor Antagonists in Vascular Smooth Muscle Cells

(±)-Govadine and (±)-THP ((±)-2,3,10,11-tetrahydroxytetrahydroprotoberberine HBr) have been shown to inhibit noradrenaline-induced contraction of rat thoracic aortae. The pharmacological activity of the compounds was determined in thoracic aortae and cardiac tissue isolated from the rat and in trachea isolated from the guinea-pig to determine the selectivity of the compounds towards different types of receptor. (±)-Govadine and (±)-THP were found to be α₁-adrenoceptor blocking agents in rat thoracic aorta as revealed by their competitive antagonism of vasoconstriction induced by noradrenaline (pA₂ = 6.57 ± 0.07 and 5.93 ± 0.06, respectively) or phenylephrine (pA₂ = 6.74 ± 0.08 and 6.06 ± 0.10, respectively). Removal of endothelium did not affect the antagonistic potencies of (±)-govadine (pA₂ = 6.83 ± 0.09) and (±)-THP (pA₂ = 6.25 ± 0.06) on phenylephrine-induced vasoconstriction. They were more potent than yohimbine (pA₂ = 6.05 ± 0.05), but less so than phentolamine (pA₂ = 7.54 ± 0.11) and prazosin (pA₂ = 9.27 ± 0.12). (±)-Govadine and (±)-THP, furthermore, inhibited [³H]inositol monophosphate formation caused by noradrenaline (3 μm ) in rat thoracic aorta. (±)-Govadine and (±)-THP were also α₂-adrenoceptor blocking agents with pA₂ values 5.50 ± 0.13 and 5.41 ± 0.11, respectively. A high concentration of (±)-govadine (30 μm ) or (±)-THP (30 μm ) did not, however, affect the contraction induced by the thromboxane receptor agonist U46619, prostaglandin F_2α (PGF_2α), 5-hydroxytryptamine (5-HT), angiotensin II, endothelin or high K⁺ in rat aorta denuded of endothelium. Neither the cyclic AMP nor cyclic GMP content of rat thoracic aorta was, furthermore, changed by (±)-govadine or (±)-THP. Contraction of guinea-pig trachea caused by carbachol, histamine, leukotriene C₄ or neurokinin A was not affected by (±)-govadine or (±)-THP. (±)-Govadine or (±)-THP also did not block β₁- or β₂-adrenoceptor-mediated responses induced by isoprenaline in rat right atria and guinea-pig trachea. It is concluded that (±)-govadine and (±)-THP are selective α₁-adrenoceptor antagonists in vascular smooth muscle.     

Synthesis of (±) 3‐(6‐nitro‐2‐quinolinyl)‐[9‐methyl‐11C]‐3,9‐diazabicyclo‐[4.2.1]‐nonane ([11C‐methyl]NS 4194)

(±) 3‐(6‐Nitro‐2‐quinolinyl)‐[9‐methyl‐¹¹C]‐3,9‐diazabicyclo‐[4.2.1]‐nonane ([¹¹C‐methyl]NS 4194), a selective serotonin reuptake inhibitor (SSRI), was synthesised within 35 min after end of bombardment with a radiochemical purity >98%. It had a decay‐corrected radiochemical yield of 7% after preparative HPLC, and a specific radioactivity around 37 GBq/μmol (EOS). A typical production starting with 40 GBq [¹¹C]CO₂ yielded 800 MBq of radiolabelled [¹¹C‐methyl]NS 4194 in a formulated solution. The synthesis of the precursor to [¹¹C‐methyl]NS 4194, (±) 9‐H‐3‐[6‐nitro‐(2‐quinolinyl)]‐3,9‐diazabicyclo‐[4.2.1]‐nonane, as well as the unlabelled analogue (±) 9‐methyl 3‐[6‐nitro‐(2‐quinolinyl)]‐3,9‐diazabicyclo‐[4.2.1]‐nonane (NS 4194), are also described. Copyright © 2002 John Wiley & Sons, Ltd.     

Synthesis of (±) [5‐3H] N′‐nitrosoanatabine,a tobacco‐specific nitrosamine

Tobacco‐specific N′‐nitrosamines (TSNA) are a unique class of systemic organ‐specific carcinogens. The TSNA are formed by N‐nitrosation of nicotine and of the minor tobacco alkaloids after harvesting of tobacco and during smoking. The N‐nitrosation of anatabine leads to N′‐nitrosoanatabine (NAT; 1‐nitroso‐1,2,3,4‐tetrahydro‐2,3'‐bipyridyl) which requires in‐depth assays in laboratory animals other than the rat. Furthermore, delineation of its tissue distribution and metabolism is needed for structure:activity comparisons with other TSNA and for the assessment of potential human risk from this TSNA. We have, therefore, synthesized (±)[5‐³H]NAT. 5‐Bromo‐3‐pyridine‐carboxaldehyde was condensed with ethyl carbamate prior to Diels–Alder reaction with 1,4‐butadiene to give the racemic anatabine ring system. Hydrolysis, followed by reduction with LiAlT₄ and nitrosation, led to (±)[5‐³H]NAT (60% yield, specific activity 266 mCi/mmol, radiochemical purity of >99%). Copyright © 2002 John Wiley & Sons, Ltd.     

Synthese der Pyrrolizidine (±)-Tussilagin und (±)-Isotussilagin

Syntheses of the Pyrrolizidines (±)-Tussilagine und (±)-Isotussilagine The syntheses of the title compounds are described. The structures of the intermediates are elucidated by IR, ¹H-NMR and mass spectroscopy.     

Radiosynthesis and in vitro evaluation of 1‐(tetrahydro‐5‐hydroxy‐6‐(hydroxymethyl)‐2H‐pyran‐3‐yl)‐5‐[125I]iodouracil: A new potential agent for HSV1‐tk reporter gene monitoring

Synthesis, radiolabelling, and in vitro evaluation of a new ¹²⁵I‐labelled iodouracil hexitol nucleoside analogue are reported. The target compound was successfully synthesized by an iodination–destannylation method and then purified by reverse phase HPLC. The radiochemical purity of the product was >99% with decay‐corrected yields of 48±3%. In vitro cellular uptake testing was carried out using MCA and MCA‐tk cell lines for comparison of compound 1 with [¹⁸F]FHBG. The newly synthesized compound 1 showed higher accumulation in herpex simplex virus type 1 thymidine kinase (HSV1‐tk) gene expression cell line (MCA‐tk cell line) than in the wild type MCA cell line compared with [¹⁸F]FHBG. The MCA‐tk to MCA cellular uptake ratio for compound 1 was higher than that of [¹⁸F]FHBG from 2 h after incubation. The radioiodine‐labelled compound 1 (I‐125, t_1/2=59.37 days) has a longer physical half‐life than F‐18‐(t_1/2=110 min) labelled FHBG. Radioiodine‐labelled compound 1 could be used for monitoring gene expression for a long time. The selectivity for MCA‐tk cell line makes compound 1 a promising imaging agent for HSV1‐tk expression. Copyright © 2010 John Wiley & Sons, Ltd.     

Synthesis of the serotonin transporter ligand (±)‐10‐methyl 3‐[6‐nitro‐(2‐quinolinyl)]‐3,10‐diazabicyclo‐[4.3.1]‐decane ([11C‐methyl]NS 2495) and first in vivo results

The serotonin transporter ligand (±)‐10‐[¹¹C]‐methyl 3‐[6‐nitro‐(2‐quinolinyl)]‐3,10‐diazabicyclo‐[4.3.1]‐decane ([¹¹C‐methyl]NS 2495) was synthesized via a methylation reaction with [¹¹C]methyl iodide. The radiochemical purity exceeded 99% and the specific radioactivity was found to be 1.8 GBq/μmol at 40 min after the end of bombardment. The uptake of the tracer in the brain of a living pig was recorded by positron emission tomography (PET), first in a baseline condition, and again after treatment with citalopram (1 mg/kg, i.v.) to displace the specific binding. The distribution volume relative to the metabolism‐corrected arterial input was high in pig brain, ranging from 75–150 ml g^?1; treatment with citalopram uniformly reduced the distribution volume to 75 ml g^?1. Binding potential (pB) maps generated using the cerebellum as a reference tissue showed highest binding in the mesencephalon and cingulate cortex, where the magnitude of pB was close to 0.6. Thus, the pattern of binding in vivo agrees with the known pattern of serotonin innervations in pig brain. However, the specific binding was incompletely displaced by pre‐treatment with citalopram. Thus, [¹¹C‐methyl]NS 2495 can label serotonin transporters in a PET study of the brain of a living pig, but full displacement by cold citalopram was not obtained in vivo, possibly reflecting binding sites which are inaccessible to citalopram. Copyright © 2003 John Wiley & Sons, Ltd.     

Synthesis,radiofluorination and first evaluation of (±)‐[18F]MDL 100907 as serotonin 5‐HT2A receptor antagonist for PET

In some psychiatric disorders 5‐HT_2A receptors play an important role. In order to investigate those in vivo there is an increasing interest in obtaining a metabolically stable, subtype selective and high affinity radioligand for receptor binding studies using positron emission tomography (PET). Combining the excellent in vivo properties of [¹¹C]MDL 100907 for PET imaging of 5‐HT_2A receptors and the more suitable half‐life of fluorine‐18, MDL 100907 was radiofluorinated in four steps using 1‐(2‐bromoethyl)‐4‐[¹⁸F]fluorobenzene as a secondary labelling precursor. The complex reaction required an overall reaction time of 140 min and (±)‐[¹⁸F]MDL 100907 was obtained with a specific activity of at least 30 GBq/µmol (EOS) and an overall radiochemical yield of 1–2%. In order to verify its binding to 5‐HT_2A receptors, in vitro rat brain autoradiography was conducted showing the typical distribution of 5‐HT_2A receptors and a very low non‐specific binding of about 6% in frontal cortex, using ketanserin or spiperone for blocking. Thus, [¹⁸F]MDL 100907 appears to be a promising new 5‐HT_2A PET ligand. Copyright © 2008 John Wiley & Sons, Ltd.     

177Lu‐labeled monomeric,dimeric and multimeric RGD peptides for the therapy of tumors expressing α(ν)β(3) integrins

The conjugation of peptides to gold nanoparticles (AuNPs) produces biocompatible and stable multimeric systems with target‐specific molecular recognition. Peptides based on the cyclic Arg‐Gly‐Asp (RGD) sequence have been reported as high‐affinity agents for the α(ν)β(3) integrin. The aim of this research was to prepare a multimeric system of ¹⁷⁷Lu‐labeled gold nanoparticles conjugated to c(RGDfK)C (cyclo(Arg‐Gly‐Asp‐Phe‐Lys)Cys) and to compare the radiation‐absorbed dose with that of ¹⁷⁷Lu‐labeled monomeric and dimeric RGD peptides to α(ν)β(3) integrin‐positive U87MG tumors in mice. DOTA‐GGC (1,4,7,10‐tetraazacyclododecane‐N‐N′,N″,N?‐tetraacetic acid‐Gly‐Gly‐Cys) and c(RGDfK)C peptides were synthesized and conjugated to AuNPs by a spontaneous reaction of the thiol groups. Transmission electron microscopy, ultraviolet–visible, X‐ray photoelectron spectroscopy, Raman and far‐infrared spectroscopy techniques demonstrated that AuNPs were functionalized with the peptides. For the ¹⁷⁷Lu‐AuNP‐c(RGDfK)C to be obtained, the ¹⁷⁷Lu‐DOTA‐GGC radiopeptide was first prepared and added to a solution of AuNPs followed by c(RGDfK)C (25 µl, 5 µ m ) at 18 °C for 15 min. ¹⁷⁷Lu‐DOTA‐GGC, ¹⁷⁷Lu‐DOTA‐cRGDfK and ¹⁷⁷Lu‐DOTA‐E‐c(RGDfK)₂ were prepared by adding ¹⁷⁷LuCl₃ (370 MBq) to 5 µl (1 mg/ml) of the DOTA derivative diluted with 50 µl of 1 m acetate buffer pH 5. The mixture was incubated at 90 °C in a block heater for 30 min. Radiochemical purity was determined by ultrafiltration and HPLC analyses. Biokinetic studies were accomplished in athymic mice with U87MG‐induced tumors. The radiochemical purity for all ¹⁷⁷Lu‐RGD derivatives was 96 ± 2%. ¹⁷⁷Lu‐absorbed doses per injected activity delivered to U87MG tumors were 0.357 ± 0.052 Gy/MBq (multimer), 0.252 ± 0.027 Gy/MBq (dimer) and 0.102 ± 0.018 Gy/MBq (monomer). ¹⁷⁷Lu‐labeled dimeric and multimeric RGD peptides demonstrated properties suitable for targeted radionuclide therapy of tumors expressing α(ν)β(3) integrins. Copyright © 2012 John Wiley & Sons, Ltd.     

Biological evaluation of selected 3,4‐dihydro‐2(1H)‐quinoxalinones and 3,4‐dihydro‐1,4‐benzoxazin‐2‐ones: Molecular docking study

In order to investigate new potential therapeutically active agents, we investigated the biological properties of two small libraries of quinoxalinones and 1,4‐benzoxazin‐2‐ones. The results obtained showed that compounds 5 , 9–11 have good cytotoxic activity against HeLa cells where the lowest IC₅₀ value (10.46 ± 0.82 μM/mL) was measured for compound 10 . Additionally, the most active compounds ( 5 , 9 – 11 ) showed much better selectivity for MRC‐5 cells (up to 17.4) compared to cisplatin. In vitro evaluation of the inhibition of the enzyme α‐glucosidase showed that compounds 10 and 11 exert significant inhibition of the enzyme at 52.54 ± 0.09 and 40.09 ± 0.49 μM, respectively. Competitive experiments with ethidium bromide (EB) indicated that all tested compounds have affinity to displace EB from the EB‐DNA complex through intercalation, suggesting good competition with EB (K_sv = (3.1 ± 0.2), (5.1 ± 0.1), (5.6 ± 0.2), and (6.3 ± 0.2) × 10³ M^?1). A molecular docking study was also performed to better understand the binding modes and to conclude the structure–activity relationships of the synthesized compounds.

     

Synthesis of (R)‐ and (S)‐[O‐methyl‐11C]N‐[2‐[3‐(2‐cyano‐phenoxy)‐2‐hydroxy‐propylamino]‐ethyl]‐N′‐(4‐methoxy‐phenyl)‐urea as candidate high affinity β1‐adrenoceptor PET radioligands

Molecular imaging and quantification of myocardial β₁‐adrenoceptor (AR) rather than total β‐AR density is of great clinical interest since cardiac biopsy studies suggest that myocardial β₁‐AR density is reduced in patients with chronic heart failure whereas cardiac β₂‐AR density may vary. Positron emission tomography (PET), with appropriate radioligands, offers the possibility to assess β‐AR density non‐invasively in humans. However, no PET radioligand for the selective imaging of cardiac β₁‐ARs is clinically available. Here some derivatives of the well characterized β₁‐AR selective antagonist, ICI 89,406, namely the enantiomers of N‐[2‐[3‐(2‐cyano‐phenoxy)‐2‐hydroxy‐propylamino]‐ethyl]‐N′‐(4‐hydroxy‐phenyl)‐urea ( 5a and 5b ) were synthesized and evaluated in vitro. The (R)‐isomer 5a was more β₁‐selective but has lower affinity than its (S)‐enantiomer 5b (β₁‐AR selectivity: 6100 vs 1240; β₁‐affinity: K₁ = 0.288 nM vs K₁ = 0.067 nM). Etherification of the analogous desmethyl precursors, 5e and 5f , respectively, with [¹¹C]iodomethane gave ¹¹C‐labelled versions of 5a and 5b , namely 5g and 5h , in 44 ± 5% radiochemical yield (decay‐corrected) and 97.4 ± 1.3% radiochemical purity with specific radioactivities of 26.4 ± 9.4 GBq/µmol within 41.2 ± 3.4 min from the end of bombardment (n = 14). 5g and 5h are now being evaluated as candidate radioligands for myocardial β₁‐ARs. Copyright © 2005 John Wiley & Sons, Ltd.     

Isotopically labelled tropane alkaloids. The synthesis of (RS)‐[3′, 3′‐2H2]‐ and (RS)‐[1′‐13C, 3′, 3′‐2H2]‐ hyoscyamines for metabolism studies in plants

A synthetic route to isotopically labelled forms of the tropane alkaloid hyoscyamine, including (RS)‐[3′, 3′,‐²H₂]‐ ( 2a ) and (RS)‐[1′‐¹³C, 3′, 3′,‐²H₂]‐ ( 2b ) hyoscyamines, involving the reaction between phenylacetyl tropine and formaldehyde is described. The isotopically labelled products enable the metabolism of hyoscyamine to be studied in plants such as Datura stramonium. Copyright © 2002 John Wiley & Sons, Ltd.     

Synthesis and in vitro evaluation of 18F‐labelled di‐ and tri(ethylene glycol) metomidate esters

By replacing the alkyl chain in a metomidate ester with ¹⁸F‐labelled di‐ or tri(ethylene glycol) chains, two ¹⁸F‐labelled PET tracers, i.e. 2‐(2‐[¹⁸F]fluoroethoxy)ethyl 1‐[(1R)‐1‐phenylethyl]‐1H‐imidazole‐5‐carboxylate (1) and 2‐[2‐(2‐[¹⁸F]fluoroethoxy)ethoxy]ethyl 1‐[(1R)‐1‐phenylethyl]‐1H‐imidazole‐5‐carboxylate (2), were synthesized. Two precursors, 2‐(2‐bromoethoxy)ethyl 1‐[(1R)‐1‐phenylethyl]‐1H‐imidazole‐5‐carboxylate and 2‐[2‐(2‐chloroethoxy)ethoxy]ethyl 1‐[(1R)‐1‐phenylethyl]‐1H‐imidazole‐5‐carboxylate, were prepared and used in one‐step nucleophilic [¹⁸F]fluorination reactions using conventional and microwave heating. Organ distribution, frozen section autoradiography and metabolite analysis were performed. The decay‐corrected radiochemical yields of 1 and 2 were 26±8 and 23±8%, respectively, when they were prepared using conventional heating. By performing microwave heating, the reaction time could be decreased and the yields of analogues 1 and 2 could be increased to 57±12 and 51±18%, respectively. Organ distribution studies in the rat showed considerable uptake in the lungs, adrenals and liver. Both compounds bound with low nonspecific binding (1: approx. 20–30%; 2: 2.9% or lower) to tissue from pig and human normal and pathologic adrenals. Metabolite analyses were performed in rats after 5 and 30 min for tracer 1 (20±6 and 2±1%) and tracer 2 (27±5 and 6±4%). Both compounds are interesting candidates for the detection of different types of adrenal disorders. Copyright © 2009 John Wiley & Sons, Ltd.     

Synthesis and calcium channel modulating effects of modified Hantzsch nitrooxyalkyl 1,4‐dihydro‐2,6‐dimethyl‐3‐nitro‐4‐(pyridinyl or 2‐trifluoromethylphenyl)‐5‐pyridinecarboxylates

A group of racemic nitrooxyalkyl 1,4‐dihydro‐2,6‐dimethyl‐3‐nitro‐4‐(pyridinyl or 2‐trifluoromethylphenyl)‐5‐pyridinecarboxylates 8a–o were synthesized using modified Hantzsch reactions. In vitro calcium channel antagonist activities, determined using a guinea pig ileum longitudinal smooth muscle (GPILSM) assay, showed that compounds 8a–o exhibited weaker calcium antagonist activity (10^–5 to 10^–7 M range) than the reference drug nifedipine (IC₅₀ = 1.43 × 10^–8 M). Compounds 8 possessing a C‐4 R¹ = 2‐pyridyl substituent were always more potent than the approximately equiactive analogs having an R¹ = 3‐pyridyl, 4‐pyridyl or 2‐CF₃‐C₆H₄‐substituent, within each subgroup of nitrooxyalkyl compounds [R² = – (CH₂)_nONO₂ (n = 2, 3, 4) or –CH(CH₂ONO₂)₂]. Although the length of the R² = –(CH₂)_nONO₂ substituent (n = 2–4) was not a determinant of smooth muscle calcium antagonist activity when the C‐4 R¹‐substituent was 2‐pyridyl, when R¹ was a 3‐pyridyl, 4‐pyridyl, or 2‐CF₃‐C₆H₄‐substituent, the relative potency order with respect to the R² = –(CH₂)_nONO₂ substituent was n = 3 and 4 > n = 2. Replacement of the isopropyl substituent of the ester moiety of the calcium antagonist (±)‐2‐pyridyl 3a by a –(CH₂)_nONO₂ (n = 2–4) moiety increased calcium antagonist activity on GPILSM by 8‐fold. In contrast, replacement of the isopropyl substituent of the ester moiety of the calcium agonists (±)‐3‐pyridyl 3b , (±)‐4‐pyridyl 3c or the methyl substituent of the ester moiety of Bay K8644 by a R² nitrooxyalkyl substituent resulted in abolition of their calcium agonist effects on GPILSM that is replaced by a smooth muscle calcium antagonist effect. These calcium antagonist data support the concept that incorporation of a nitrooxyalkyl ester substituent constitutes a valuable drug design strategy to enhance Hantzsch 1,4‐dihydropyridine calcium antagonist and/or abolish calcium agonist effects on smooth muscle. Replacement of the isopropyl ( 8b–c ), or the methyl ( 8d ) group by a –CH₂CH₂ONO₂ moiety resulted in retention of the cardiac positive inotropic effect where the relative potency order with respect to the C‐4 substituent was 2‐CF₃‐C₆H₆‐ (8d) > 3‐pyridyl (8b) ≈ 4‐pyridyl (8c). Model hybrid (calcium channel modulation, ·NO release) compounds, that exhibit dual cardioselective agonist / smooth muscle selective antagonist activities, represent a novel type of 1,4‐dihydropyridine CC modulator that offers a potential approach to drug discovery targeted toward the treatment of congestive heart failure and for use as probes to study the structure–function relationship of calcium channels. Drug Dev. Res. 51:225–232, 2000. © 2001 Wiley‐Liss, Inc.     

Synthesis of an 18F‐labelled high affinity β1‐adrenoceptor PET radioligand based on ICI 89,406

To date, some non‐selective β‐adrenoceptor (β‐AR) positron emission tomography (PET) radioligands are in clinical use, but no PET radioligand for the selective imaging of cardiac β₁‐ARs is clinically available. Therefore, the aim of this study was to develop a potential high‐affinity PET radioligand for the β₁‐subtype of ARs. Here, the synthesis and in vitro evaluation of (S)‐ and (R)‐N‐[2‐[3‐(2‐cyano‐phenoxy)‐2‐hydroxy‐propylamino]‐ethyl]‐N′‐[4‐(2‐fluoro‐ethoxy)‐phenyl]‐urea ( 8a–b ), derivatives of the well‐characterized β₁‐AR selective antagonist, ICI 89,406, are described. The (S)‐isomer 8a shows both higher β₁‐AR selectivity and β₁‐AR affinity than the (R)‐enantiomer 8b (selectivity: 40 800 vs 1580; affinity: K_I1=0.049 nM vs K_I1=0.297 nM). Therefore, the ¹⁸F‐labelled analogue 8e of compound 8a was synthesized. While the direct nucleophilic ¹⁸F‐fluorination of the tosylate precursor 8d produced 8e in low radiochemical yields (?2.9% decay‐corrected) and specific activities (?3.5 GBq/µmol at the end of synthesis (EOS), n=9) the alternative two‐step synthesis of 8e from ethylene glycol di‐p‐tosylate 9 , [¹⁸F]fluoride ion and phenol precursor 8f gave satisfying results (16.4±3.2% radiochemical yield (decay‐corrected), 99.7±0.5% radiochemical purity, 40±8 GBq/µmol specific activity at the EOS within 174±3 min from the end of bombardment (EOB) (n=5)). Copyright © 2006 John Wiley & Sons, Ltd.     

Synthesis and 11C‐labelling of (E,E)‐1‐(3′,4′‐dihydroxystyryl)‐4‐(3′‐methoxy‐4′‐hydroxystyryl) benzene for PET imaging of amyloid deposits†

Carboxylic acid derivatives of the amyloid‐binding dye Congo red do not enter the brain well and are thus unable to serve as in vivo amyloid‐imaging agents. A neutral amyloid probe, (E,E)‐1‐(3′,4′‐dihydroxystyryl)‐4‐(3′‐methoxy‐4′‐hydroxystyryl)benzene ( 3 ), devoid of any carboxylate groups has been designed and synthesized via a 12‐step reaction sequence with a total yield of 30%. The unsymmetric compound 3 has also been labelled with C‐11 via [¹¹C]methyl iodide ([¹¹C]CH₃I) methylation of a symmetric 4,4′‐dimesyl protected precursor followed by deprotection. Preliminary evaluation indicated that compound 3 selectively stained plaques and neurofibrillary tangles in post‐mortem AD brain, and exhibited good binding affinity (K_i=38±8 nM) for Aβ(1–40) fibrils in vitro. In vivo pharmacokinetic studies indicated that [¹¹C] 3 exhibited higher brain uptake than its carboxylic acid analogs and good clearance from normal control mouse brain. [¹¹C] 3 also exhibited specific in vivo binding to pancreatic amyloid deposits in the NOR‐beta transgenic mouse model. These results justify further investigation of 3 and similar derivatives as surrogate markers for in vivo quantitation of amyloid deposits. Copyright © 2002 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.     

Eumelanin is a Major Determinant for2‐Amino‐1‐methyl‐6‐phenylimidazo[4,5‐b]pyridine (PhIP) Incorporation into Hair of Mice

Mice with different hair pigmentation were studied to evaluate the role of melanin in the incorporation of 2‐amino‐1‐methyl‐6‐phenylimidazo[4,5‐b]pyridine (PhIP) into hair. Mice C57BL/6J‐c2j/+ (white), C57BL/6J‐Ay (yellow), C57L/J (grey), C57BR/cdJ (brown) and C57BL/6J (black) were dosed with PhIP: 7–9 days old (total amount: 0.006 or 0.58 mg/kg b.wt., for 4 days) and adults (total amount 50 mg/kg b.wt. during 8 weeks). Hair was collected either 30 days after the last PhIP administration (new‐born mice) or 8 weeks after the first administration (adult mice). PhIP was incorporated into black hair to a greater extent than into brown, grey, yellow and non‐pigmented hair. The concentration of PhIP in the hair of new‐born mice exposed to 0.58 mg PhIP/kg b.wt. were (mean±S.D.): 328±135 (black), 134±41 (brown), 9.1±1.2 (yellow) and 5.2±1.4 (white) ng/g hair. The PhIP concentrations in the hair of adult mice exposed to 50 mg/kg b.wt. were: 4750±1449 (black), 810±235 (brown), 541±119 (grey), 35.5±4.6 (yellow) and 21.6±8.8 (white) ng/g, and the eumelanin hair concentration in the same animals decreased in a similar pattern. A linear relationship (r²=1.00, P<0.0001) between the relative PhIP incorporation and the eumelanin concentration in hair was found.     

Synthesis of deuterium‐labelled (−)‐galanthamine

The synthesis of deuterium‐labelled galanthamine is reported. 6‐[²H₃]methoxy‐N‐[²H₃]methyl‐(?)‐galanthamine was obtained in seven steps from galanthamine. The synthesis was carried out by selective O‐ and N‐demethylations. The [²H₃]‐N‐methyl and [²H₃]‐O‐methyl‐groups were introduced by selective aminoreduction and O‐methylation. Copyright © 2008 John Wiley & Sons, Ltd.