Synthesis and evaluation of novel 18F‐labeled quinazoline derivatives with low lipophilicity for tumor PET imaging

Four novel ¹⁸F‐labeled quinazoline derivatives with low lipophilicity, [¹⁸F]4‐(2‐fluoroethoxy)‐6,7‐dimethoxyquinazoline ( [ ¹⁸ F]I ), [¹⁸F]4‐(3‐((4‐(2‐fluoroethoxy)‐7‐methoxyquinazolin‐6‐yl)oxy)propyl)morpholine ( [ ¹⁸ F]II ), [¹⁸F]4‐(2‐fluoroethoxy)‐7‐methoxy‐6‐(2‐methoxyethoxy)quinazoline ( [ ¹⁸ F]III ), and [¹⁸F]4‐(2‐fluoroethoxy)‐6,7‐bis(2‐methoxyethoxy)quinazoline ( [ ¹⁸ F]IV ), were synthesized via a 2‐step radiosynthesis procedure with an overall radiochemical yield of 10% to 38% (without decay correction) and radiochemical purities of >98%. The lipophilicity and stability of labeled compounds were tested in vitro. The log P values of the 4 radiotracers ranged from 0.52 to 1.07. We then performed ELISA to measure their affinities to EGFR‐TK; ELISA assay results indicated that each inhibitor was specifically bounded to EGFR‐TK in a dose‐dependent manner. The EGFR‐TK autophosphorylation IC₅₀ values of [ ¹⁸ F]I , [ ¹⁸ F]II , [ ¹⁸ F]III , and [ ¹⁸ F]IV were 7.732, 0.4698, 0.1174, and 0.1176 μM, respectively. All labeled compounds were evaluated via cellular uptake and blocking studies in HepG2 cell lines in vitro. Cellular uptake and blocking experiment results indicated that [ ¹⁸ F]I and [ ¹⁸ F]III had excellent cellular uptake at 120‐minute postinjection in HepG2 carcinoma cells (51.80 ± 3.42%ID/mg protein and 27.31 ± 1.94%ID/mg protein, respectively). Additionally, biodistribution experiments in S180 tumor‐bearing mice in vivo indicated that [ ¹⁸ F]I had a very fast clearance in blood and a relatively high uptake ratio of tumor to blood (4.76) and tumor to muscle (1.82) at 60‐minute postinjection. [ ¹⁸ F]III had a quick clearance in plasma, and its highest uptake ratio of tumor to muscle was 2.55 at 15‐minute postinjection. These experimental results and experiences were valuable for the further exploration of novel radiotracers of quinazoline derivatives.     

4‐Substituted‐1‐phenyl‐1H‐pyrazolo[3,4‐d]pyrimidine Derivatives: Design,Synthesis, Antitumor and EGFR Tyrosine Kinase Inhibitory Activity

Four series of some 4‐substituted‐1‐phenyl‐1H‐pyrazolo[3,4‐d]pyrimidine derivatives 5a – f , 6a – f , 8a – f , and 9a – f were designed to be screened for their antitumor activity. All compounds were evaluated against breast (MCF‐7) and lung (A‐549) cell lines. Six compounds 5a , 5b , 6b , 6e , 9e , and 9f displaying activity against both cell lines were further estimated for their EGFR‐TK inhibitory activity where they revealed 41–91% inhibition and compound 6b elicited the highest activity (91%). A docking study of these compounds into the ATP‐binding site of EGFR‐TK demonstrated their binding mode where H‐bonding interaction with Met793 through N¹ of pyrimidine or N² of pyrazole was observed.     

Synthesis and labeling of a piperazine‐based library of 11C‐labeled ligands for imaging of the vesicular acetylcholine transporter

The cholinergic system is involved in neurodegenerative diseases, and visualization of cholinergic innervations with positron emission tomography (PET) would be a useful tool in understanding these diseases. A ligand for the vesicular acetylcholine transporter (VAChT), acknowledged as a marker for cholinergic neurons, could serve as such a PET tracer. The aim was to find a VAChT PET tracer using a library concept to create a small but diverse library of labeled compounds. From the same precursor and commercially available aryl iodides 6a–f, six potential VAChT PET tracers, [¹¹C]‐(±)5a–f, were ¹¹C‐labeled by a palladium (0)‐mediated aminocarbonylation, utilizing a standard protocol. The labeled compounds [¹¹C]‐(±)5a–f were obtained in radiochemical purities >95% with decay‐corrected radiochemical yields and specific radioactivities between 4–25% and 124–597 GBq/µmol, respectively. Autoradiography studies were then conducted to assess the compounds binding selectivity for VAChT. Labeled compounds [¹¹C]‐(±)5d and [¹¹C]‐(±)5e showed specific binding but not enough to permit further preclinical studies. To conclude, a general method for a facile synthesis and labeling of a small piperazine‐based library of potential PET tracers for imaging of VAChT was shown, and in upcoming work, another scaffold will be explored using this approach     

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.     

Efficient synthesis of [11C]befloxatone,a selective radioligand for the in vivo imaging of MAO‐A density using PET

Carbon‐11 labelled befloxatone ((5R)‐5‐(methoxymethyl)‐3‐[4‐[(3R)‐4,4,4‐trifluoro‐3‐hydroxybutoxy]phenyl]‐2‐oxazolidinone) is a reversible and selective monoamine oxidase‐A (MAO‐A) inhibitor and appears to be a new potent PET tracer for the in vivo imaging of MAO‐A density. In this paper, the radiosynthesis of befloxatone was investigated and orientated towards the preparation of multi milliCuries of radiotracer. Typically, using no‐carrier‐added [¹¹C]phosgene, 150–300 mCi (5.55–11.10 GBq) of [¹¹C]befloxatone was obtained within 20 min of radiosynthesis (including HPLC purification) with specific radioactivities ranging from 500 to 2000 mCi/µmol (18.5–74.0 GBq/µmol). The high efficiency of these radiosyntheses allows for multi‐injection protocols and kinetic approaches for absolute quantification of the tracer. Copyright © 2003 John Wiley & Sons, Ltd.     

Synthesis and radiosynthesis of N5‐[18F]fluoroethyl‐Pirenzepine and its metabolite N5‐[18F]fluoroethyl‐LS 75

The well established M₁ selective muscarinergic antagonist Pirenzepine 11‐[2‐(4‐methyl‐piperazin‐1‐yl)‐acetyl]‐5,11‐dihydro‐benzo[e]pyrido[3,2‐b][1,4]diazepin‐6‐one (1) exhibits an unusual behaviour in vivo, which cannot be explained with M₁ antagonism exclusively. One of the aspects discussed is a specific interaction with poly ADP‐ribose polymerase (PARP‐1). 1 undergoes metabolism to form LS 75 5,11‐dihydro‐benzo[e]pyrido[3,2‐b][1,4]diazepin‐6‐one (2). In order to study deviations in Pirenzepine efficacy from pure M₁ binding in vivo using PET, appropriate positron emitter labelled analogues of 1 and 2 were synthesised. Non‐radioactive reference compounds 3 and 4 were tested for PARP‐1 inhibition. The n‐octanol–water partition coefficients of compounds 1, 2, 3 and 4 at pH 7.4 (logD_7.4) were determined. Both, 3 and 4 were labelled with ¹⁸F via 2‐[¹⁸F]fluoroalkylation in position 5 of the benzodiazepinone moiety to obtain N⁵‐[¹⁸F]fluoroethyl Pirenzepine [¹⁸F]‐3 and N⁵‐[¹⁸F]fluoroethyl LS 75 [¹⁸F]‐4. Radiotracers [¹⁸F]‐3 and [¹⁸F]‐4 were obtained in radiochemical yields of 15±4 % and 30±5% after 120 and 110 min, respectively. Metabolism of both compounds was investigated in vitro in human and rat plasma, respectively. Compound 3 did not show activity as an inhibitor of PARP‐1. Contrary, 4 displays moderate PARP‐1 inhibition potency. The new radiotracer [¹⁸F]‐4 can be applied for molecular imaging using autoradiography and PET. Copyright © 2009 John Wiley & Sons, Ltd.     

Synthesis and biological evaluation of carbon‐11‐labeled acyclic and furo[2,3‐d]pyrimidine derivatives of bicyclic nucleoside analogues (BCNAs) for structure–brain uptake relationship study of BCNA tracers

We reported earlier on radiolabeled alkoxyphenyl bicyclic nucleoside analogues (BCNAs) as potential positron emission tomography (PET) reporter probes for imaging of varicella zoster virus thymidine kinase (VZV‐tk) gene in vivo. Despite their favorable physicochemical properties, these tracers are not taken up in the brain in mice. In order to probe the role of the deoxyribose sugar moiety in blood‐brain barrier (BBB) penetration of these molecules, we have synthesized and evaluated a carbon‐11‐labeled acyclic bicyclic nucleoside derivative ([¹¹C]‐10) where the 2′‐deoxyribose sugar is replaced with a (2‐hydroxyethoxy)methyl group and [¹¹C]‐12, which has no sugar moiety but a [¹¹C]methyl group on the N‐3 position of the pyrimidine ring. Methylation was achieved on the phenol ([¹¹C]‐10) or the N‐3 position ([¹¹C]‐12) using [¹¹C]methyl triflate (radiosynthesis). The (non‐radioactive) acyclic O‐methyl derivative 10 has rather poor affinity for the enzyme VZV‐TK in vitro (IC₅₀: 430 µM), compared with the moderate affinity of the BCNA‐base N‐methyl derivative 12 (IC₅₀: 79 µM). In normal mice, none of the two tracers ([¹¹C]‐10 or [¹¹C]‐12) showed significant uptake in the brain, suggesting that compounds containing a furo[2,3‐d]pyrimidine system do not cross the BBB. Copyright © 2008 John Wiley & Sons, Ltd.     

F‐18 labelled N,N‐bis‐haloethylamino‐phenylsulfoxides — a new class of compounds for the imaging of hypoxic tissue

Two N,N‐bis‐chloroethylamino‐phenylsulfoxides have been synthesized and radiolabelled with F‐18 via halogen exchange. The radiolabelling of both compounds proceeds smoothly with K[¹⁸F]F‐kryptofix 2.2.2 complex at 100 °C in DMSO. Decay‐corrected radiochemical yields were 25–35% for [¹⁸F] 12 (SO201) and 35–45% for [¹⁸F] 11 (SO101), with an average specific activity of 1.8 Ci/µmol. Both compounds remained 80% intact in plasma over a period of 2 h. In vivo binding in a stroke model indicates that both markers are selectively retained in hypoxic tissue. Copyright © 2006 John Wiley & Sons, Ltd.     

Synthesis,labelling and first evaluation of [18F]R91150 as a serotonin 5‐HT2A receptor antagonist for PET

In psychiatric disorders such as anxiety, depression and schizophrenia, 5‐HT_2A receptors play an important role. In order to investigate them in vivo there is an increasing interest in selective and high‐affinity radioligands for receptor binding studies using positron emission tomography (PET). Since available radioligands have disadvantages, R91150, which is a selective and high‐affinity ligand for 5‐HT_2A receptors, was labelled with fluorine‐18. This was accomplished in six steps via 4‐[¹⁸F]fluorophenol and 1‐(3‐bromopropoxy)‐4‐[¹⁸F]fluorobenzene within 190 min starting from no‐carrier‐added [¹⁸F]fluoride. The overall radiochemical yield was 3.8±2% and the specific activity was at least 335 GBq/µmol at the end of the synthesis. First ex vivo studies in mice proved the uptake of [¹⁸F]R91150 in the brain. Radiometabolite studies revealed no radiometabolites in the brain, whereas in the plasma at least two could be detected 30 min p.i. Further preclinical studies are encouraged to evaluate the potential of this new 5‐HT_2A ligand as a radiotracer for PET. Copyright © 2008 John Wiley & Sons, Ltd.     

Radiolabeling of ginkgolide B with 18F

Ginkgolide B, a terpene trilactone constituent of Gingko biloba extracts and an antagonist for the platelet activating factor (PAF) receptor, was radiolabeled with the positron emitter ¹⁸F for visualizing its in vivo behavior using positron emission tomography (PET). The 7‐[¹⁸F]fluoro analog of ginkgolide B (7‐¹⁸FGB) was synthesized via nucleophilic displacement of the triflate group at C7 with [¹⁸F]fluoride. The reaction was complete in 5–10 min, affording 7‐¹⁸FGB in an average radiochemical yield of approximately 16% (decay corrected). The average specific activity at E.O.S. was approximately 40 GBq/µmol, and the radiochemical and chemical purity was greater than 95%. Copyright © 2004 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.     

Fluorine‐18 labeling of ML04 – presently the most promising irreversible inhibitor candidate for visualization of EGFR in cancer

Overexpression of the EGFR has been linked to cell malignancy, metastasis and poor prognosis thus making it a target for several FDA approved drugs such as Gefitinib and Erlotinib. Unfortunately, these drugs have yielded suboptimal clinical results. In order to evaluate and monitor EGFR‐targeted treatment response at the molecular level, several PET biomarkers have been developed. One of the lead irreversible inhibitors (1) has been labeled with carbon‐11, however the short half‐life of this radioisotope limited the time window for in vivo studies. Compound 1 was successfully labeled with fluorine‐18 via a multi‐step radiosynthesis with 14% decay‐corrected overall radiochemical yield, 98% radiochemical purity, specific activity of 1800 Ci/mmol (n=10) at end of bombardment, and a total radiosynthesis time of 4 h including purification and formulation. [ ¹⁸ F] ‐ 1 will allow for prolonged in vivo studies including Micro‐PET analysis of EGFR tumor‐bearing animal models. Copyright © 2006 John Wiley & Sons, Ltd.     

Synthesis,labelling and evaluation of hydantoin‐substituted indole carboxylic acids as potential ligands for positron emission tomography imaging of the glycine binding site of the N‐methyl‐d‐aspartate receptor

The N‐methyl‐ d ‐aspartate (NMDA) receptor as a type of ionotropic glutamatergic receptors is essential for physiological processes such as learning, memory and synaptic plasticity. A glutamate‐induced overactivation of these receptors, accompanied by increased intracellular calcium concentration, causes cell injury and leads to a large number of acute or chronic neurological disorders, such as stroke, trauma, Parkinson's disease and Alzheimer's disease. In an attempt to visualise the glutamatergic neurotransmission in vivo with positron emission tomography, novel fluoroethoxy‐ and methoxy‐substituted reference compounds based on the lead structure of a hydantoin‐substituted indole‐2‐carboxylic acid were synthesised. The affinities towards the glycine binding site of the NMDA receptor showed K_i values between 322 and 11 nM and the lipophilicities ranged from logD values of 1.51 to 2.53. On the basis of these results, precursor compounds were synthesised containing a phenolic hydroxy moiety to obtain the radiolabelled ligands through an alkylation reaction. Radiosynthesis was achieved by labelling the precursor ethyl 4,6‐dichloro‐3‐((3‐(4‐hydroxyphenyl)‐2,4‐dioxoimidazolidin‐1‐yl)methyl)‐indole‐2‐carboxylate with 2‐[¹⁸F]fluoroethyl tosylate or [¹¹C]methyl iodide and subsequent cleavage of the ethyl ester moiety. This gave the final products in overall decay‐corrected radiochemical yields of 5–7% and 6–9% and specific activities of 24–67 GBq/µmol and 8–26 GBq/µmol, respectively.     

Synthesis of [18F]3‐[1‐(3‐fluoropropyl)‐(S)‐pyrrolidin‐2‐ylmethoxy]pyridine ([18F]NicFP): a potential α4β2 nicotinic acetylcholine receptor radioligand for PET

Nicotinic acetylcholine receptors are widely distributed throughout the human brain and are believed to play a role in several neurological and psychiatric disorders. In order to identify an effective PET radioligand for in vivo assessment of the α4β2 subtype of nicotinic receptor, we synthesized [¹⁸F]3‐[1‐(3‐fluoropropyl)‐(S)‐pyrrolidin‐2‐ylmethoxy]pyridine (NicFP). The in vitro K_D of NicFP was determined to be 1.1 nM, and the log P value obtained by HPLC analysis of the unlabelled standard was found to be 2.2. The radiosynthesis of [¹⁸F]NicFP was carried out by a nucleophilic substitution reaction of anhydrous [¹⁸F]fluoride and the corresponding mesylate precursor. After purification by HPLC, the radiochemical yield was determined to be 11.3±2.1% and the specific activity was 0.47±0.18 Ci/μmol (EOS, n = 3). The time of synthesis and purification was 99±2 min. The final product was prepared as a sterile saline solution suitable for in vivo use. Copyright © 2003 John Wiley & Sons, Ltd.     

Synthesis and structural identification of fluorine‐18 labeled parathyroid hormone

Parathyroid hormone (PTH) is an 84 amino acid peptide hormone that plays a key role in bone and mineral metabolism. The biological actions of PTH are mediated via the N‐terminal PTH(1–34) fragment, serving as the PTH receptor‐binding sequence, and which is therefore used clinically to treat conditions of low bone mass such as osteoporosis. In this study, PTH(1–34) was conjugated with non‐radioactive (stable F isotope) N‐succinimidyl 4‐fluorobenzoate (SFB) leading to three isomeric mono‐fluorobenzoated (FBz) PTH followed by Liquid chromatography‐Tandem mass spectrometry (LC‐MS/MS) assisted structural identification. Corresponding [¹⁸F]SFB‐labeled PTH derivatives were prepared respectively and the Lys¹³ site‐specific labeled [¹⁸F]FBz PTH was isolated by HPLC with radiochemical purity >99% and specific activity of 2.78 GBq/µmol, suitable for future application with in vivo pharmacokinetic/pharmacodynamic studies of PTH, using preclinical Positron Emission Tomography Computed Tomography (PET/CT) imaging.     

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 biological evaluation of [carboxyl‐11C]eprosartan

Essential hypertension occurs in approximately 25% of the adult population and one cause of hypertension is primary aldosteronism. Targeting the angiotensin II AT₁ receptor using PET and an appropriate tracer may offer a diagnostic method for adrenocortical tissue. This report describes the synthesis of the selective AT₁ receptor antagonist [carboxyl‐¹¹C]eprosartan 10, 4‐[2‐butyl‐5‐((E)‐2‐carboxy‐3‐thiophen‐2‐yl‐propenyl)‐imidazol‐1‐ylmethyl]‐[carboxyl‐¹¹C]benzoic acid, and its precursor (E)‐3‐[2‐butyl‐3‐(4‐iodo‐benzyl)‐3H‐imidazol‐4‐yl]‐2‐thiophen‐2‐ylmethyl‐acrylic acid 9. ¹¹C‐carboxylation of the iodobenzyl moiety was performed using a palladium‐mediated reaction with [¹¹C]carbon monoxide in the presence of tetra‐n‐butyl‐ammonium hydroxide in a micro‐autoclave using a temperature gradient from 25 to 140°C over 5 min. After purification by semipreparative HPLC, [carboxyl‐¹¹C]eprosartan 10 was obtained in 37–54% decay‐corrected radiochemical yield (from [¹¹C]carbon monoxide) with a radiochemical purity >95% within 35 min of the end of bombardment (EOB). A 5‐µAh bombardment gave 2.04 GBq of 10 (50% rcy from [¹¹C]carbon monoxide) with a specific activity of 160 GBq µmol^?1 at 34 min after EOB. Frozen‐section autoradiography shows specific binding in kidney, lung and adrenal cortex. In vivo experiments in rats demonstrate a high accumulation in kidney, liver and intestinal wall. Copyright © 2009 John Wiley & Sons, Ltd.     

A novel radiochemical approach to 1‐(2'‐deoxy‐2'‐[18F]fluoro‐β‐d‐arabinofuranosyl)cytosine (18F‐FAC)

¹⁸F‐FAC (1‐(2'‐deoxy‐2'‐[¹⁸F]fluoro‐β‐D‐arabinofuranosyl)‐cytosine) is an important 2'‐fluoro‐nucleoside‐based positron emission tomography (PET) tracer that has been used for in vivo prediction of response to the widely used cancer chemotherapy drug gemcitabine. Previously reported synthetic routes to ¹⁸F‐FAC have relied on early introduction of the ¹⁸F radiolabel prior to attachment to protected cytosine base. Considering the ¹⁸F radiochemical half‐life (110 min) and the technical challenges of multi‐step syntheses on PET radiochemistry modular systems, late‐stage radiofluorination is preferred for reproducible and reliable radiosynthesis with in vivo applications. Herein, we report the first late‐stage radiosynthesis of ¹⁸F‐FAC. Cytidine derivatives with leaving groups at the 2'‐position are particularly prone to undergo anhydro side‐product formation upon heating because of their electron density at the 2‐carbonyl pyrimidone oxygen. Our rationally developed fluorination precursor showed an improved reactivity‐to‐stability ratio at elevated temperatures. ¹⁸F‐FAC was obtained in radiochemical yields of 4.3–5.5% (n = 8, decay‐corrected from end of bombardment), with purities ≥98% and specific activities ≥63 GBq/µmol. The synthesis time was 168 min.     

One‐Pot Laccase‐Catalysed Synthesis of 5,6‐Dihydroxylated Benzo[b]furans and Catechol Derivatives,and Their Anticancer Activity

A commercial laccase, Suberase® from Novozymes, was used to catalyse the synthesis of 5,6‐dihydroxylated benzo[b]furans and catechol derivatives. The yields were, in some cases, similar to or better than that obtained by other enzymatic, chemical or electrochemical syntheses. The synthesised derivatives were screened against renal (TK10), melanoma (UACC62), breast (MCF7) and cervical (HeLa) cancer cell lines. GI₅₀, TGI and LC₅₀ are reported for the first time. Anticancer screening showed that the cytostatic effects of the 5,6‐dihydroxylated benzo[b]furans were most effective against the melanoma (UACC62) cancer cell line with several compounds exhibiting potent growth inhibitory activities (GI₅₀ = 0.77–9.76 µM), of which two compounds had better activity than the anticancer agent etoposide (GI₅₀ = 0.89 µM). One compound exhibited potent activity (GI₅₀ = 9.73 µM) against the renal (TK10) cancer cell line and two exhibited potent activity (GI₅₀ = 8.79 and 9.30 µM) against the breast (MCF7) cancer cell line. These results encourage further studies of the 5,6‐dihydroxylated benzo[b]furans for their potential application in anticancer therapy.     

Synthesis of [11C]gefitinib for imaging epidermal growth factor receptor tyrosine kinase with positron emission tomography

We have synthesized N‐(3‐chloro‐4‐fluorophenyl)‐7‐[¹¹C]methoxy‐6‐[3‐(morpholin‐4‐yl)propoxy]quinazolin‐4‐amine, [¹¹C]gefitinib ([¹¹C]Iressa), a high affinity (IC₅₀ = 2 nM) inhibitor of the epidermal growth factor receptor tyrosine kinase (EGFR‐TK), in solution and in a semi‐automated stainless loop methylation system using [¹¹C]methyl triflate. The trapping efficiency for [¹¹C]methyl triflate in solution was higher than in the solvent film generated in the loop system, thus the overall radiochemical yield was considerably higher for the synthesis in solution. The average radiochemical yield for the solution chemistry was 15% with an average specific radioactivity of approximately 9000 mCi/µmole at EOS in one step from its corresponding desmethyl phenol precursor. Copyright © 2006 John Wiley & Sons, Ltd.