Potential Positron Emission Tomography Research Articles

Facile synthesis of new carbon-11 labeled conformationally restricted rivastigmine analogues as potential PET agents for imaging AChE and BChE enzymes

Rivastigmine is a newer-generation inhibitor with a dual inhibitory action on both acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) enzymes, and is used for the treatment of AChE- and BChE-related diseases such as brain Alzheimer's disease and cardiovascular disease. New carbon-11 labeled conformationally restricted rivastigmine analogues radiolabeled quaternary ammonium triflate salts, (3a R,9b S)-1-[ 11C]methyl-1-methyl-6-(methylcarbamoyloxy)-2,3,3a,4,5,9b-hexahydro-1 H-benzo[g]indolium triflate ([ 11C] 8) and (3a R,9b S)-1-[ 11C]methyl-1-methyl-6-(heptylcarbamoyloxy)-2,3,3a,4,5,9b-hexahydro-1 H-benzo[g]indolium triflate ([ 11C] 9), were designed and synthesized as potential positron emission tomography (PET) agents for imaging AChE and BChE enzymes. The appropriate precursors were labeled with [ 11C]CH 3OTf through N-[ 11C]methylation, and the target tracers were isolated by solid-phase extraction (SPE) using a cation-exchange CM Sep-Pak cartridge in 40–50% radiochemical yields decay corrected to end of bombardment (EOB), 15–20 min overall synthesis time, and 148–222 GBq/μmol specific activity at EOB.

Novel Fluorinated Derivatives of the Broad-Spectrum MMP Inhibitors N-Hydroxy-2(R)-[[(4-methoxyphenyl)sulfonyl](benzyl)- and (3-picolyl)-amino]-3-methyl-butanamide as Potential Tools for the Molecular Imaging of Activated MMPs with PET

An approach to the in vivo imaging of locally upregulated and activated matrix metalloproteinases (MMPs) found in many pathological processes is offered by positron emission tomography (PET). Hence, appropriate PET radioligands for MMP imaging are required. Here, we describe the syntheses of novel fluorinated MMP inhibitors (MMPIs) based on lead structures of the broad-spectrum inhibitors N-hydroxy-2(R)-[[(4-methoxyphenyl)sulfonyl](benzyl)-amino]-3-methyl-butanamide (CGS 25966) and N-hydroxy-2(R)-[[(4-methoxyphenyl)sulfonyl](3-picolyl)-amino]-3-methyl-butanamide (CGS 27023A). Additionally, tailor-made precursor compounds for radiolabeling with the positron-emitter 18F were synthesized. All prepared hydroxamate target compounds showed high in vitro MMP inhibition potencies for MMP-2, MMP-8, MMP-9, and MMP-13. As a consequence, the promising fluorinated hydroxamic acid derivative 1f was resynthesized in its 18F-labeled version via two different procedures yielding the potential PET radioligand [18F]1f. As expected, the biodistribution behavior of this novel compound and that of the more hydrophilic variant [18F]1j, also developed by our group, indicates that there was no tissue specific accumulation in wild-type (WT) mice.

Synthesis and biological evaluation in rat and cat of [18F]12ST05 as a potential 5-HT6 PET radioligand

5-hydroxytryptamine (5-HT)6 receptors represent one of the more recently discovered serotoninergic receptor family. However, no 5-HT6 positron emission tomography (PET) radiotracer is currently used in clinical imaging studies. The purpose of this study was to propose the first fluorinated PET radiotracer for this brain receptor. A new compound presenting in vitro high affinity towards the serotoninergic 5-HT6 receptor, N-[2-(1-[(4-fluorophenyl)sulfonyl]-1H-indol-4-yloxy)ethyl]-N,N-dimethylamine, was labelled with fluorine 18 via a nitro-/fluoronucleophilic substitution. Biological evaluations included (i) in vitro and ex vivo autoradiographies in rat brain and (ii) a PET scan on anaesthetized cat. Although the radioligand showed excellent brain penetration, it did not reveal any specific binding to the 5-HT6 receptors indicating that this radiotracer is not suitable for mapping 5-HT6 receptors using PET.

Species differences in mGluR5 binding sites in mammalian central nervous system determined using in vitro binding with [18F]F-PEB

Binding of [18F]3-fluoro-5-[(pyridin-3-yl)ethynyl]benzonitrile ([18F]F-PEB) was evaluated in membranes and tissue sections prepared from rat, rhesus and human brain. Saturation equilibrium binding experiments with frozen brain cortex and caudate-putamen membranes of young adult rhesus and human and with cortex and striatum from rat yielded data indicative of specific high-affinity binding (KD=0.1-0.15 nM, n> or =3) to a saturable site previously shown to be metabotropic glutamate receptor 5 (mGluR5; Patel S, Ndubizu O, Hamill T, Chaudhary A, Burns HD, Hargreaves RJ, Gibson RE. Screening cascade and development of potential positron emission tomography radiotracers for mGluR5: in vitro and in vivo characterization. Mol Imaging Biol 2005;7:314-323). High-affinity binding of [18F]F-PEB was also detected in cerebellum membranes from rat, rhesus and human. The density of binding sites (Bmax) measured using [18F]F-PEB followed the rank order cortex approximately caudate-putamen/striatum>cerebellum for all three species, with the cerebellum Bmax being significantly lower than that observed in the other regions. Receptor autoradiography studies in tissue sections confirmed that the regional distribution of [18F]F-PEB in mammalian central nervous system is consistent with that of mGluR5 and that a small but specific mGluR5 signal is observed in rhesus and human cerebellum. A small and quantifiable specific signal could also be observed in rat cerebellum using this radiotracer. Immunohistochemical analysis in brain sections revealed a rank order of staining in rhesus and human brain of cortex approximately caudate-putamen>cerebellum. Rat brain immunohistochemistry followed the same rank order, although the staining in the cerebellum was significantly lower. Using a "no-wash" wipe assay, the development of a specific signal within 20 min of incubation of tissue brain sections (>60% in the cortex and striatum; 36-49% in the cerebellum) from all three species confirmed previous in vivo data from rat and rhesus monkey that [18F]PEB is likely to provide a useful in vivo signal using positron emission tomography (PET). This study provides the first quantitative demonstration and direct comparison of a PET tracer candidate identifying mGluR5 binding sites in mammalian cerebellum, which subsequently raises questions in terms of using the cerebellum as a null tissue in PET imaging studies in the laboratory and the clinic.

Synthesis of N‐(2,5‐dimethoxybenzyl)‐N‐(5‐fluoro‐2‐phenoxyphenyl)[carbonyl‐11C]acetamide ([carbonyl‐11C]DAA1106) and analogues using [11C]carbon monoxide and palladium(0) complex

AbstractN‐(2,5‐Dimethoxybenzyl)‐N‐(5‐fluoro‐2‐phenoxyphenyl)acetamide (DAA1106), a potent and selective ligand for peripheral benzodiazepine receptor, and eight structurally related analogues were labelled with 11C at the carbonyl position using a low concentration of [11C]carbon monoxide and the micro‐autoclave technique. A combinatorial approach was applied to synthesize the analogues using similar reaction conditions. Palladium‐mediated carbonylation using tetrakis(triphenylphosphine)palladium, various amines and methyl iodide or iodobenzene was employed in the synthesis. The 11C‐labelled products were obtained with 10–55% decay‐corrected radiochemical yields and the final product was more than 97% pure in all cases. Specific radioactivity was determined for the compound [carbonyl‐11C]DAA1106 using a single experiment and a 10‐µA h bombardment. The specific radioactivity, measured 36 min after end of bombardment, was 455 GBq/µmol. Synthetic routes to the precursors and reference compounds were also developed. The presented approach is a novel method for the synthesis of [carbonyl‐11C]DAA1106 and its analogues, and allows the formation of a library of 11C‐labelled DAA1106 analogues which can be used to optimize the performance as a potential positron emission tomography tracer. Copyright © 2007 John Wiley & Sons, Ltd.

Track structure simulation for positron emitters of physical interest. Part III: The case of the non-standard radionuclides

With the growth of clinical Positron Emission Tomography (PET) utilizations, new molecular tracers, able to aid in the assessment, therapy planning and monitoring of cancer patients, are synthesized. As suggested by some works reported in the literature, these newcomers may be positron emitting isotopes of lanthanium, 134La, iodine, 120I, 121I and 124I, arsenic, 72As and 74As, oxygen, 14O, and neon, 19Ne. In this work, we present an inter comparison of these eight radiopharmaceuticals which may be used in PET. To do that we have used a Monte Carlo simulation of positron following-up in water that we have adapted to the beta decay of radionuclides. We have also access to accurate spatial and energetic distributions of the potential PET radiopharmaceuticals under investigation here. The results are given in an analytical way and have been compared, when possible, with theoretical and experimental values available in the literature.

Synthesis of carbon-11 labeled 1-(3,4-dimethoxybenzyl)-2,2-dimethyl-1,2,3,4-tetrahydroisoquinolinium derivatives as new potential PET SK Ca channel imaging agents

Small conductance Ca 2+-activated K + (SK Ca) channels play an important role in many functions such as neuronal communication and behavioral plasticity, secretion, and cell proliferation. SK Ca channel modulation is associated with various brain, heart, and cancer diseases. N-methyl-laudanosine and its structurally related derivatives, substituted 1-(3,4-dimethoxybenzyl)-2,2-dimethyl-1,2,3,4-tetrahydroisoquinoliniums, are reversible and selective SK Ca channel blockers. Carbon-11 labeled N-methyl-laudanosine and its tetrahydroisoquinolinium derivatives may serve as new probes for positron emission tomography (PET) to image SK Ca channels in the brain, heart, and cancer. The key intermediates, substituted isoquinolines ( 3a–c), were synthesized using a modification of the Pomeranz–Fritsch procedure. The precursors, substituted 1-(3,4-dimethoxybenzyl)-2-methyl-1,2,3,4-tetrahydroisoquinolines ( 8a–c), and their corresponding reference standards, substituted 1-(3,4-dimethoxybenzyl)-2,2-dimethyl-1,2,3,4-tetrahydroisoquinoliniums ( 9a–c), were synthesized from compounds 3a–c with 3,4-dimethoxybenzyl chloride ( 2) in multiple steps with moderate to excellent chemical yields. The precursor 6,7-dimethoxy-1-(3,4-dimethoxybenzyl)-2-methyl-1,2,3,4-tetrahydroisoquinoline ( 10) was commercially available, and the methylation of compound 10 with methyl iodide provided N-methyl-laudanosine ( 11). The target quaternary ammonium tracers, carbon-11 labeled 1-(3,4-dimethoxybenzyl)-2,2-dimethyl-1,2,3,4-tetrahydroisoquinoliniums ([ 11C] 9a–c and [ 11C] 11), were prepared by N-[ 11C]methylation of the tertiary amine precursors ( 8a–c and 10) with [ 11C]methyl triflate and isolated by a simplified solid-phase extraction (SPE) purification using a SiO 2 or cation-exchange CM Sep-Pak cartridge in 40–65% radiochemical yields.

3D-QSAR of PET Agents for Imaging β-Amyloid in Alzheimer's Disease

Accumulation of excess senile plaques (β-amyloid, Aβplaques) in the brain is strongly associated with the pathogenesis of Alzheimer’s disease (AD). While there are no definitive treatments available to affect a cure of AD, much recent interest has been given to the development of antiamyloid therapies aimed at halting and reversing Aβ-deposition and, thus, monitoring of the therapeutic efficacy would greatly benefit from methods for the in vivo detection and quantification of Aβ-deposits in the brain. Several groups have reported a series of potential imaging agents for the in vivo imaging of Aβ-plaques with positron emission tomography (PET) or single-photon emission computed tomography (SPECT). However, to our knowledge, no three dimensional structure activity relationship (3D-QSAR) studies on PET ligands have been published so far with the exception of CoMFA/CoMSIA study on serotonin transporter (SERT) ligands, and the aim of the present study was to quantitatively investigate structure-activity relationships (SAR) of PET ligands with regard to the future development of potential new PET radiotracers by using Comparative Molecular Field Analysis (CoMFA) and Comparative Molecular Similarity Indices Analysis (CoMSIA). In this study, we constructed a 3D-QSAR model with several PET ligands such as ThioT analogues and stilbene derivatives, which could be applied to predict binding affinity of the structurally related compounds against Aβplaques. From the literature, binding affinity data of 62 ThioT derivatives and 11 stilbene derivatives were obtained which were used for model building (Fig. 1). At first, the 73 compounds obtained from the literature were divided into two groups: 63 compounds as training set and the other 10 compounds as test set. The training set was used to build 3D-QSAR models with CoMFA and CoMSIA methods, while the test set was used to validate the 3D-

New 2α-tropane amides as potential PET ligands for the dopamine transporter

Positron emission tomography (PET) imaging of dopamine transporter (DAT) density in the brain is a potentially valuable tool for studying the etiopathology of degenerative brain disorders. The present study evaluated five new potential competitive inhibitors of DAT as ligands for PET. The evaluation of the new compounds measured their ability to compete with the binding of the reference ligand 2beta-carbomethoxy-3beta-(4-[(131)I]iodophenyl)tropane [(131)I]beta-CIT to striatal and cortical membranes from rat and pig brain. Four of the new compounds structurally related to cocaine were synthesized in their 2alpha,3beta configuration; the most potent one, 3beta-(4-iodo-phenyl)-8-methyl-8-aza-bicyclo[3.2.1]octane-2alpha-carboxylic acid (2-fluoro-ethyl)-amide, was synthesized also in the 2beta,3beta configuration. For comparative studies in rat brain and new evaluation in pig brain homogenate, the established compounds beta-CIT, FP-CIT, PE2I and FETT were also synthesized and evaluated. Contrary to expectation, the 2alpha,3beta and 2beta,3beta isomers of 3-(4-iodo-phenyl)-8-methyl-8-aza-bicyclo[3.2.1]octane-2-carboxylic acid (2-fluoro-ethyl)-amide showed the same affinity constant for rat striatum (K(i)=200 nM+/-34), but in pig striatum and rat and pig cortex the 2alpha,3beta form even had a higher affinity than the 2beta,3beta form.

Synthesis of carbon-11 labeled biaryl 1,2,3,4-tetrahydroisoquinoline derivatives and conformationally flexible analogues as new potential PET glioma tumor imaging agents

Carbon-11 labeled biaryl 1,2,3,4-tetrahydroisoquinoline derivatives and conformationally flexible analogues, 2-(2-(biphenyl-4-yl)ethyl)-6-[ 11C]methoxy-7-methoxy-1,2,3,4-tetrahydroisoquinoline ([ 11C] 3); 1-(biphenyl-4-yl)methyl-6,7-dimethoxy-2-[ 11C]methyl-1,2,3,4-tetrahydroisoquinoline ( N-[ 11C] 7) and 1-(biphenyl-4-yl)methyl-6-[ 11C]methoxy-7-methoxy-2-methyl-1,2,3,4-tetrahydroisoquinoline ( O-[ 11C] 7); and 2-(biphenyl-4-yl)- N-(3,4-dimethoxy-phenethyl)- N-[ 11C]methyl-ethanamine ( N-[ 11C] 10) and 2-(biphenyl-4-yl)- N-(3-methoxy-4-[ 11C]methoxy-phenethyl)- N-methyl-ethanamine ( O-[ 11C] 10), have been synthesized as new potential positron emission tomography (PET) glioma tumor imaging agents, either by O-[ 11C]methylation or by N-[ 11C]methylation of the appropriate precursors using [ 11C]CH 3OTf and isolated either by a simplified solid-phase extraction (SPE) purification procedure or by HPLC method in 30–55% radiochemical yields decay corrected to EOB, 15–25 min overall synthesis time, and 4.0–6.0 Ci/μmol specific activity at EOB.

Pre vivo, ex vivo and in vivo evaluations of [68Ga]-EDTMP

The objectives of this study were to develop a simple preparation method for [68Ga]-EDTMP and to evaluate the applicability of [68Ga]-EDTMP as a potential positron emission tomography (PET) bone imaging agent using pre vivo, ex vivo and in vivo models. [68Ga]-EDTMP was prepared using 68Ga]-gallium chloride eluted from the 68Ge/68Ga generator and commercially available Multibone kits. Binding affinity to bone compartments was evaluated using a recently established pre vivo model. In vivo (microPET) and ex vivo experiments were performed in mice, and the results of which were compared with those obtained with [18F]-fluoride. [68Ga]-EDTMP was accessible via simple kit preparation and predominantly accumulated in bone tissue in vivo, ex vivo and pre vivo. Binding to mineral bone was irreversible, and low binding was observed in organic bone. In vivo microPET evaluation revealed predominant uptake in bone with renal excretion. Compared with [18F]-fluoride, the uptake was lower and the PET image quality was reduced. From the present evaluation, apart from the autonomy for PET centers without an onsite cyclotron, the advantage of [68Ga]-EDTMP over [18F]-fluoride is not apparent and the future clinical prospect of [68Ga]-EDTMP remains speculative.

Synthesis and Binding Affinity of a Fluorine-Substituted Peroxisome Proliferator-Activated Gamma (PPARγ) Ligand as a Potential Positron Emission Tomography (PET) Imaging Agent

The peroxisome proliferator-activated receptor gamma (PPARgamma) is an important regulator of lipid metabolism and the differentiation of pre-adipocytes. Thus, imaging PPARgamma in vivo using positron-emission tomography (PET) might be useful in assessing lipid metabolism disorders and identifying tumor cell differentiation. A fluorine-substituted PPARgamma ligand from tyrosine-benzophenone class, compound 1, has a very high affinity for PPARgamma receptor (Ki = 0.14 nM). To develop this compound as a PPARgamma PET imaging agent, we investigated synthetic routes suitable for its labeling with the short-lived PET radionuclide fluorine-18 (t1/2 = 110 min). To obtain the high specific activity material needed for receptor imaging with this isotope, reactions need to proceed efficiently, within a short time, starting from fluoride ion at the tracer level. The most promising approach involves introduction of fluorine into a suitable benzophenone precursor, followed by efficient coupling of this intermediate with the heterocyclic tyrosine component using a copper-catalyzed Ullmann-type condensation.

Evaluation of Primary Brain Tumors With FLT-PET: Usefulness and Limitations

The purpose of this report was to investigate the potential of positron emission tomography using F-18 fluorodeoxythymidine (FLT-PET) in evaluating primary brain tumors. FLT-PET was performed in 25 patients with primary brain tumors. FLT uptake in the lesion was semiquantitatively evaluated by measuring the maximal standardized uptake value (SUVmax) and the tumor-to-normal tissue ratio (TNR). SUVmax and TNR were compared with the histologic grade and the expression of the proliferation marker (Ki-67). FLT uptake in normal brain parenchyma was very low, resulting in the visualization of brain tumors with high contrast. Both SUVmax and TNR significantly correlated with the malignant grade of brain gliomas, in which high SUVmax/TNR was obtained for high-grade gliomas. Patients with primary lymphoma also showed SUVmax/TNR equivalent to glioblastoma. There was a positive correlation between SUVmax/TNR and the Ki-67 index. In contrast, spuriously high SUVmax and TNR were obtained in 3 of 6 patients with suspected recurrent tumors (2 patients with recurrent grade 2 glioma and one patient with postoperative granuloma), all of which showed lesion enhancement on MRI after Gd administration. FLT-PET can be used to evaluate the malignant grade and proliferation activity of primary brain tumors, especially malignant brain tumors. However, the presence of benign lesions showing blood-brain barrier disruption cannot be distinguished from malignant tumors and needs to be carefully evaluated.

In vitro and in vivo evaluation of [11C]MPEPy as a potential PET ligand for mGlu5 receptors

Excessive activation via the metabotropic glutamate receptor subtype 5 (mGluR(5)) has been implicated in depression, neuropathic pain and other psychiatric, neurological and neurodegenerative diseases. A mGluR(5) radioligand for in vivo quantification by positron emission tomography (PET) would facilitate studies of the role of this receptor in disease and treatment. 3-Methoxy-5-pyridin-2-ylethynylpyridine (MPEPy), a selective and high-affinity antagonist at the mGluR(5) receptor was selected as a candidate ligand; a recent publication by Yu et al. [Nucl Med Biol 32 (2005) 631-640] presented initial micro-PET results for [(11)C]MPEPy with enthusiasm. Building on their efforts, we report as unique contributions (1) an improved chemical synthesis method, (2) the first data using human tissue, (3) phosphor images for rat brain preparations, (4) a novel comparison of anesthetic agents and (5) in vivo data in baboon. In vitro phosphor imaging studies of this ligand using human and rat brain tissue demonstrated high specific binding in the hippocampus, striatum and cortex with minimal specific binding in the cerebellum. In contrast, in vivo micro-PET studies in rats using urethane anesthesia, PET studies in baboons using isoflurane anesthesia and ex vivo micro-PET studies in unanesthetized rats each showed little specific binding in the brain. Despite the promising in vitro results, the low signal-to-noise ratio found in vivo does not justify the use of [(11)C]MPEPy as a PET radiotracer in humans.

Synthesis of carbon-11 labeled fluorinated 2-arylbenzothiazoles as novel potential PET cancer imaging agents

Fluorinated 2-arylbenzothiazoles are new potential antitumor drugs, which show potent and selective inhibitory activity against breast, lung, and colon cancer cell lines. Carbon-11 labeled fluorinated 2-arylbenzothiazoles may serve as novel probes for positron emission tomography (PET) to image tyrosine kinase in cancers. The preparation of 4-fluorinated 2-arylbenzothiazoles 4-fluoro-2-(3-benzloxy-4-methoxyphenyl)benzothiazole ( 6a) and 4-fluoro-2-(3,4-dimethoxyphenyl)benzothiazole ( 6b) was achieved by a modification of Jacobson thioanilide radical cyclization chemistry. Hydrogenolytic cleavage of the benzyl ether group of compound 6a using H 2/Pd–C provided the precursor 4-fluoro-2-(3-hydroxy-4-methoxyphenyl)benzothiazole ( 7) for radiolabeling. Synthesis of radiolabeling precursors and the reference standards 5- and 6-fluorinated arylbenzothiazoles ( 11c–n) was achieved via the reaction of o-aminothiophenol disulfides with substituted benzaldehydes under reducing conditions. The target radiotracers carbon-11 labeled 4-, 5-, and 6-fluorinated arylbenzothiazoles (3-[ 11C] 6b, 4-[ 11C] 11c, 3-[ 11C] 11c, 5-[ 11C] 11f, 4-[ 11C] 11f, 4-[ 11C] 11i, 3-[ 11C] 11i, 5-[ 11C] 11l, and 4-[ 11C] 11l) were prepared by O-[ 11C]methylation of the phenolic hydroxyl precursors ( 7, 11d, 11e, 11g, 11h, 11j, 11k, 11m, and 11n) with [ 11C]methyl triflate and isolated by solid-phase extraction (SPE) purification in 30–55% radiochemical yields.

Synthesis and biological evaluation of potential positron emission tomography (PET) ligands for brain visualization of dopamine D3 receptors

Currently, the lack of a selective dopamine D3 PET (positron emission tomography) radioligand for in vivo brain occupancy studies is problematic. Several requirements are necessary for a potential PET radioligand for visualization of a receptor into the brain: i) high affinity and selectivity for the target receptor; ii) suitable lipophilicity for both blood-brain barrier permeation and low nonspecific binding to proteins and lipids; iii) structural features that allow labelling with a positron emission isotope. In this study the synthesis and binding affinities for dopamine D3 and D2 receptors of several N-[4-(4-arylpiperazin-1-yl)butyl]arylcarboxamides are reported. These compounds were designed by the structural modification of the formerly reported D3 receptor ligand N-[4-[4-(2,3-dichlorophenyl)piperazin-1-yl]butyl]-7-methoxy-2benzofurancarboxamide (1), with the aim to obtain a suitable lipophilicity and the structural features for labelling. In particular, both the 2,3-dichlorophenyl group and the 7-methoxy-2benzofurancarboxamide moiety were replaced by less lipophilic fragments. Among the studied compounds, derivatives N-[4-[4-(5-methoxy-2-benzisoxazolyl)piperazin-1-yl]butyl]-4-(4morpholinyl)benzamide (20), N-[4-[4-(5-methoxy-2-benzisoxazolyl)piperazin-1-yl]butyl]-4-(1Himidazol-1-yl)benzamide (21), and N-[4-[4-(5-methoxy-2-benzisoxazolyl)piperazin-1-yl]butyl]5-(2-furanyl)-1H-pyrazole-3-carboxamide (22) displayed good D3 receptor affinities (Ki values 38, 22.6, and 21.3 nM, respectively) and were found to be inactive at D2 receptor. Moreover, on the basis of their experimental log P values and their ability to cross the Caco-2 monolayer, compounds 20-22 are likely to permeate the blood-brain barrier, differently from compound 1.

Synthesis of Carbon-11 Labeled Triphenylacetamides as Novel Potential PET Melanoma Cancer Imaging Agents

New carbon-11 labeled triphenylacetamides (TPAs), N-(4-[ 11 C]methoxyphenyl)-2,2,2-triphenyl-acetamide ([ 11 C]MTA) and 3-phenyl-(R)-2-(2,2,2-triphenylacetylamino)propionic acid [ 11 C]methyl ester ([C]PAME), were designed and synthesized as potential positron emission tomography (PET) melanoma cancer imaging agents. The single crystal structure of the potent anti-melanoma agent, N-(4-methoxyphenyl)-2,2,2-triphenylacetamide (MTA) is reported.

Synthesis of [ 11C]Iressa as a new potential PET cancer imaging agent for epidermal growth factor receptor tyrosine kinase

Iressa (Gefitinib) is an orally active inhibitor of epidermal growth factor receptor tyrosine kinase (EGFR-TK) involved in cell signal transduction processes critical to proliferation, apoptosis, repair, and angiogenesis of cancer cells. [ 11C]Iressa was first designed and synthesized as a new potential positron emission tomography (PET) cancer imaging agent for EGFR-TK in 30–40% radiochemical yield with 4.0–6.0 Ci/μmol specific activity at end of bombardment (EOB).

Cognitive dysfunction and emotional–behavioural changes in MS: The potential of positron emission tomography

Cognitive dysfunction and emotional–behavioral changes are symptoms with increasing clinical relevance during progression of the disease. They cannot be explained by demyelination of white matter alone but clearly indicate cortical dysfunction. Positron emission tomography (PET) provides methods to assess cortical dysfunction quantitatively by measuring cerebral glucose metabolism using the tracer 18F-2-fluoro-2-deoxy- d-glucose (FDG). The technique has been employed to study fatigue and disease progression. Microglial activation was studied by 11C-PK-11195 PET. It was found not only in active plaques but also in degenerating fibre tracks. Other tracers offer a broad spectrum of measuring local physiological functions and pathophysiological processes, but some of them are still limited to experimental animal research.

Novel Benzofuran Derivatives for PET Imaging of β-Amyloid Plaques in Alzheimer's Disease Brains

A novel series of benzofuran derivatives as potential positron emission tomography (PET) tracers targeting amyloid plaques in Alzheimer's disease (AD) were synthesized and evaluated. The syntheses of benzofurans were successfully achieved by an intramolecular Wittig reaction between triphenylphosphonium salt and 4-nitrobenzoyl chloride. When in vitro binding studies using AD brain gray matter homogenates were carried out with a series of benzofuran derivatives, all the derivatives examined displayed high binding affinities with K(i) values in the subnanomolar range. Among these benzofuran derivatives, compound 8, 5-hydroxy-2-(4-methyaminophenyl)benzofuran, showed the lowest K(i) value (0.7 nM). In vitro fluorescent labeling of AD sections with compound 8 intensely stained not only amyloid plaques, but also neurofibrillary tangles. The (11)C labeled compound 8, [(11)C]8, was prepared by reacting the normethyl precursor, 5-hydroxy-2-(4-aminophenyl)benzofuran, with [(11)C]methyl triflate. The [(11)C]8 displayed moderate lipophilicity (log P = 2.36), very good brain penetration (4.8%ID/g at 2 min after iv injection in mice), and rapid washout from normal brains (0.4 and 0.2%ID/g at 30 and 60 min, respectively). In addition, this PET tracer showed in vivo amyloid plaque labeling in APP transgenic mice. Taken together, the data suggest that a relatively simple benzofuran derivative, [(11)C]8, may be a useful candidate PET tracer for detecting amyloid plaques in the brains of patients with Alzheimer's disease.