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ABSTRACT: BACKGROUND: Respiratory gating and gate optimization strategies present solutions for overcoming image degradation caused by respiratory motion in PET and traditionally utilize hardware systems and/or employ complex processing algorithms. In this work, we aimed to advance recently emerging data-driven gating methods and introduce a new strategy for optimizing the four-dimensional data based on information contained in that data. These algorithms are combined to form an automated motion correction workflow. METHODS: Software-based gating methods were applied to a nonspecific population of 84 small-animal rat PET scans to create respiratory gated images. The gated PET images were then optimized using an algorithm we introduce as 'gating+' to reduce noise and optimize signal; the technique was also tested using simulations. Gating+ is based on a principle of only using gated information if and where it adds a net benefit, as evaluated in temporal frequency space. Motion-corrected images were assessed quantitatively and qualitatively. RESULTS: Of the small-animal PET scans, 71% exhibited quantifiable motion after software gating. The mean liver displacement was 3.25 mm for gated and 3.04 mm for gating+ images. The (relative) mean percent standard deviations measured in background ROIs were 1.53, 1.05, and 1.00 for the gated, gating+, and ungated values, respectively. Simulations confirmed that gating+ image voxels had a higher probability of being accurate relative to the corresponding ungated values under varying noise and motion scenarios. Additionally, we found motion mapping and phase decoupling models that readily extend from gating+ processing. CONCLUSIONS: Raw PET data contain information about motion that is not currently utilized. In our work, we showed that through automated processing of standard (ungated) PET acquisitions, (motion-) information-rich images can be constructed with minimal risk of noise introduction. Such methods have the potential for implementation with current PET technology in a robust and reproducible way.
EJNMMI research. 04/2013; 3(1):29.
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ABSTRACT: We present a first study of the use of 11C-acetate (ACET) positron emission tomography (PET)/computed tomography (CT) in bladder urothelial carcinoma (UC) and an intraindividual comparison with 11C-choline (CHOL) PET/CT.
Fourteen patients with biopsy-proven UC (11 T2, 3 T1 refractory to treatment) were prospectively evaluated before radical cystectomy and excision of pelvic lymph nodes (LNs), with ACET and CHOL PET/CT scans performed within 1 week. Image acquisition started 5 minutes after intravenous injection of 12 to 14 mCi for both tracers. Standardized uptake values (SUVs) and tumor-to-background ratios (TBR) were calculated for all tumor and nodal findings and correlated with histopathology and follow-up.
ACET and CHOL were taken up in all UCs, involved LNs, and prostate pathology. SUVs were on average slightly, nonsignificantly higher for CHOL uptake (SUV) in UCs and significantly higher for ACET in LNs. TBR was nonsignificantly higher with CHOL for UC and significantly higher for LNs.
In this preliminary series, 11C-ACET and 11C-CHOL PET/CT showed equivalent results in the preoperative evaluation of UC. Both tracers have the potential to contribute to selecting patients who would benefit from combined treatment--neoadjuvant chemotherapy and surgery--by identifying pathologic LNs or from surgery only, thanks to their high negative predictive value for LN involvement.
Clinical nuclear medicine 04/2012; 37(4):e67-72. · 3.92 Impact Factor
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ABSTRACT: Phage display has identified the dodecapeptide YHWYGYTPQNVI (GE11) as a ligand that binds to the epidermal growth factor receptor (EGFR) but does not activate the receptor. Here, we compare the EGFR binding affinities of GE11, EGF, and their polyethyleneimine-polyethyleneglycol (PEI-PEG) conjugates. We found that although GE11 by itself does not exhibit measurable affinity to the EGFR, tethering it to PEI-PEG increases its affinity markedly, and complex formation with polyinosine/cytosine (polyIC) further enhances the affinity to the submicromolar range. PolyIC/PPGE11 has a similar strong antitumor effect against EGFR overexpressing tumors in vitro and in vivo, as polyIC/polyethyleneimine-polyetheleneglycol-EGF (polyIC/PP-EGF). Absence of EGFR activation, as previously shown by us and easier production of GE11 and GE11 conjugates, confer polyIC/PPGE11 a significant advantage over similar EGF-based polyplexes as a potential therapy of EGFR overexpressing tumors.
International Union of Biochemistry and Molecular Biology Life 02/2012; 64(4):324-30. · 3.51 Impact Factor
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ABSTRACT: BACKGROUND: Due to the limited availability of suitable positron emission tomography (PET) tracers, the majority of myocardial perfusion imaging (MPI) scans is performed using SPECT rather than PET. AIM: The aim of this study is to design and synthesize carbon-11-labeled ammonium salt derivatives and explore their structure-activity relationship (SAR) and their potential as PET-MPI agents. METHODS AND RESULTS: Three carbon-11-labeled ammonium salts were developed. SAR of the labeled compounds were explored vis-à-vis the effects of charge density and lipophilicity on the distribution kinetics in mice. These studies pointed at [(11)C]4 as the lead compound. Comparative microPET/CT scans in healthy rats, using both [(11)C]4 and [(13) N]-NH(3), substantiated the potential of [(11)C]4 ([(11)C]-DMDPA). A proof of concept for the potential of radiolabeled ammonium salts as MPI agents has been demonstrated in a newly developed swine model of permanent partial coronary artery occlusion. CONCLUSIONS: SAR studies of (11)C-labeled ammonium salts suggest that both lipophilicity and charge density affect the performance of these compounds as MPI probes. In a swine model, the labeled lead successfully visualized the defect regions in the myocardium. The data presented call for the development of fluorine-18 analogues, to increase clinical impact.
Molecular imaging and biology: MIB: the official publication of the Academy of Molecular Imaging 01/2012; · 2.47 Impact Factor
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Yodphat Krausz,
Rina Rubinstein,
Liat Appelbaum, Eyal Mishani,
Marina Orevi,
Merav Fraenkel,
Sagi Tshori,
Benjamin Glaser,
Moshe Bocher,
Asher Salmon,
Roland Chisin,
David J Gross,
Nanette Freedman
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ABSTRACT: Gallium-68 (Ga-68) DOTA-1-NaI3-octreotide (DOTA-NOC) positron emission tomography (PET)/computed tomography (CT) is increasingly used for neuroendocrine tumors (NETs), often found primarily in the pancreas. However, physiologic uptake of DOTA-NOC has been described in the uncinate process of the pancreas. We studied DOTA-NOC uptake in this organ.
Ninety-six patients underwent 103 DOTA-NOC scans, with pathology-proven pancreatic NET (n = 40) and nonpancreatic NET or biochemical suspicion of NET (n = 63).
DOTA-NOC uptake was detected in 35 documented pancreatic tumor sites (SUV: 5.5-165; mean: 25.7 ± 28.8; median: 17.8). Among 63 cases without previous known pathology, uptake was suspicious for tumor in 24 sites (SUV: 4.7-35; mean 16.3 ± 8.0; median: 14.1), and in 38 sites, it was judged as physiological, generally lower relative to adjacent structures (SUV: 2.2-12.6; mean: 6.6 ± 2.2; median: 6.2). In 24 scans with suspected tumor and in 37 of 38 scans with physiological uptake, diagnostic computed tomography or magnetic resonance imaging or endoscopic ultrasonography failed to detect tumor.
Pancreatic DOTA-NOC uptake must be interpreted with caution, and further studies are required.
Clinical nuclear medicine 01/2012; 37(1):57-62. · 3.92 Impact Factor
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Judith Magenheim,
Ohad Ilovich,
Alon Lazarus,
Agnes Klochendler,
Oren Ziv,
Roni Werman,
Ayat Hija,
Ondine Cleaver, Eyal Mishani,
Eli Keshet,
Yuval Dor
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ABSTRACT: How organ size and form are controlled during development is a major question in biology. Blood vessels have been shown to be essential for early development of the liver and pancreas, and are fundamental to normal and pathological tissue growth. Here, we report that, surprisingly, non-nutritional signals from blood vessels act to restrain pancreas growth. Elimination of endothelial cells increases the size of embryonic pancreatic buds. Conversely, VEGF-induced hypervascularization decreases pancreas size. The growth phenotype results from vascular restriction of pancreatic tip cell formation, lateral branching and differentiation of the pancreatic epithelium into endocrine and acinar cells. The effects are seen both in vivo and ex vivo, indicating a perfusion-independent mechanism. Thus, the vasculature controls pancreas morphogenesis and growth by reducing branching and differentiation of primitive epithelial cells.
Development 09/2011; 138(21):4743-52. · 6.60 Impact Factor
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Yodphat Krausz,
Nanette Freedman,
Rina Rubinstein,
Efraim Lavie,
Marina Orevi,
Sagi Tshori,
Asher Salmon,
Benjamin Glaser,
Roland Chisin, Eyal Mishani,
David J Gross
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ABSTRACT: Recent data have indicated that ⁶⁸Ga-DOTA-NOC positron emission tomography/X-ray computed tomography (PET/CT) may yield improved images in a shorter acquisition protocol than ¹¹¹In-DTPA-octreotide (OctreoScan®, OCT). Therefore, we performed a prospective comparison of ⁶⁸Ga-DOTA-NOC and OCT for the detection of neuroendocrine tumors (NETs).
Nineteen patients (eight carcinoid, nine pancreatic NETs, and two NE carcinoma of unknown origin) with previous positive OCT scans underwent ⁶⁸Ga-DOTA-NOC PET/CT and OCT single-photon emission computed tomography imaging for staging or follow-up. Findings were compared by region and verified with conventional imaging.
All images of both modalities demonstrated focal uptake, often at multiple sites. ⁶⁸Ga-DOTA-NOC images were clearer than OCT images, facilitating interpretation. Similar foci were identified with both modalities in 41 regions, with additional foci on ⁶⁸Ga-DOTA-NOC in 21 and on OCT in 15 regions. CT, magnetic resonance imaging, or ultrasound confirmed the concordant findings in 31 of 41 regions and findings seen with ⁶⁸Ga-DOTA-NOC only in 15 of 21 regions. Findings seen with OCT only were less clear and were only confirmed in 4 of 15 regions. ⁶⁸Ga-DOTA-NOC had impact on staging in four patients and on management in three patients.
Although ⁶⁸Ga-DOTA-NOC and OCT images were similar, in this study, ⁶⁸Ga-DOTA-NOC demonstrated more true positive tumor foci and was better tolerated by patients. This direct comparison supports replacement of OCT with ⁶⁸Ga-DOTA-NOC-PET/CT in the evaluation of NETs.
Molecular imaging and biology: MIB: the official publication of the Academy of Molecular Imaging 06/2011; 13(3):583-93. · 2.47 Impact Factor
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ABSTRACT: Blood vessels have been shown to play perfusion-independent roles in organogenesis. Here, we examined whether blood vessels determine branching stereotypy of the mouse lung airways in which coordinated branching of epithelial and vascular tubes culminates in their co-alignment. Using different ablative strategies to eliminate the lung vasculature, both in vivo and in lung explants, we show that proximity to the vasculature is indeed essential for patterning airway branching. Remarkably, although epithelial branching per se proceeded at a nearly normal rate, branching stereotypy was dramatically perturbed following vascular ablation. Specifically, branching events requiring a rotation to change the branching plane were selectively affected. This was evidenced by either the complete absence or the shallow angle of their projections, with both events contributing to an overall flat lung morphology. Vascular ablation also led to a high frequency of ectopic branching. Regain of vascularization fully rescued arrested airway branching and restored normal lung size and its three-dimensional architecture. This role of the vasculature is independent of perfusion, flow or blood-borne substances. Inhibition of normal branching resulting from vascular loss could be explained in part by perturbing the unique spatial expression pattern of the key branching mediator FGF10 and by misregulated expression of the branching regulators Shh and sprouty2. Together, these findings uncovered a novel role of the vasculature in organogenesis, namely, determining stereotypy of epithelial branching morphogenesis.
Development 06/2011; 138(11):2359-68. · 6.60 Impact Factor
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ABSTRACT: We have recently generated lipophilic D-xylose derivatives that increase the rate of glucose uptake in cultured skeletal muscle cells in an AMP-activated protein kinase (AMPK)-dependent manner. The derivative 2,4:3,5-dibenzylidene-D-xylose-diethyl dithioacetal (EH-36) stimulated the rate of glucose transport by increasing the abundance of glucose transporter-4 in the plasma membrane of cultured myotubes. The present study aimed at investigating potential antihyperglycaemic effects of EH-36 in animal models of diabetes. Two animal models were treated subcutaneously with EH-36: streptozotocin-induced diabetes in C57BL/6 mice (a model of insulin-deficient type 1 diabetes), and spontaneously diabetic KKAy mice (Kuo Kondo rats carrying the A(y) yellow obese gene; insulin-resistant type 2 diabetes). The in vivo biodistribution of glucose in control and treated mice was followed with the glucose analogue 2-deoxy-2-[(18) F]-D-glucose; the rate of glucose uptake in excised soleus muscles was measured with [(3) H]-2-deoxy-D-glucose. Pharmacokinetic parameters were determined by non-compartmental analysis of the in vivo data. The effective blood EH-36 concentration in treated animals was 2 μM. It reduced significantly the blood glucose levels in both types of diabetic mice and also corrected the typical compensatory hyperinsulinaemia of KKAy mice. EH-36 markedly increased glucose transport in vivo into skeletal muscle and heart, but not to adipose tissue. This stimulatory effect was mediated by Thr(172) -phosphorylation in AMPK. Biochemical tests in treated animals and acute toxicological examinations showed that EH-36 was well tolerated and not toxic to the mice. These findings indicate that EH-36 is a promising prototype molecule for the development of novel antidiabetic drugs.
Journal of Cellular and Molecular Medicine 05/2011; 16(3):594-604. · 4.13 Impact Factor
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ABSTRACT: Positron emission tomography (PET) has clear advantages over single photon emission computed tomography (SPECT) in the field of myocardial perfusion scintigraphy (MPS); however, there are just a small number of efficient PET tracers available today for MPS. We sought to develop and perform a preliminary biological evaluation of novel carbon-11-labeled ammonium salts as potential MPS PET agents.
Three potential tracers were labeled and evaluated via biodistribution in mice and PET imaging in both rats and rabbits, and the results obtained were also compared to agents that are routinely used in the clinical practice.
The results designated carbon-11-labeled ammonium salts as having great potential as MPS PET agents. Specifically, carbon-11-labeled trimethyl-phenyl-ammonium iodide ([(11)C]2) and homologues of higher lipophilicity/charge warrant further studies in larger animals and humans such as measurements of myocardial uptake at rest and stress under both normal and pathological coronary flow conditions.
Molecular imaging and biology: MIB: the official publication of the Academy of Molecular Imaging 02/2011; 13(1):128-39. · 2.47 Impact Factor
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Fredrik Wolfhagen Sand,
Andreas Hörnblad,
Jenny K Johansson,
Christina Lorén,
Josefina Edsbagge,
Anders Ståhlberg,
Judith Magenheim,
Ohad Ilovich, Eyal Mishani,
Yuval Dor,
Ulf Ahlgren,
Henrik Semb
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ABSTRACT: Endoderm development is dependent on inductive signals from different structures in close vicinity, including the notochord, lateral plate mesoderm and endothelial cells. Recently, we demonstrated that a functional vascular system is necessary for proper pancreas development, and that sphingosine-1-phosphate (S1P) exhibits the traits of a blood vessel-derived molecule involved in early pancreas morphogenesis. To examine whether S1P(1)-signaling plays a more general role in endoderm development, S1P(1)-deficient mice were analyzed. S1P(1) ablation results in compromised growth of several foregut-derived organs, including the stomach, dorsal and ventral pancreas and liver. Within the developing pancreas the reduction in organ size was due to deficient proliferation of Pdx1(+) pancreatic progenitors, whereas endocrine cell differentiation was unaffected. Ablation of endothelial cells in vitro did not mimic the S1P(1) phenotype, instead, increased organ size and hyperbranching were observed. Consistent with a negative role for endothelial cells in endoderm organ expansion, excessive vasculature was discovered in S1P(1)-deficient embryos. Altogether, our results show that endothelial cell hyperplasia negatively influences organ development in several foregut-derived organs.
Developmental Biology 01/2011; 352(2):267-77. · 4.07 Impact Factor
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Maria A Pantaleo, Eyal Mishani,
Cristina Nanni,
Lorena Landuzzi,
Stefano Boschi,
Giordano Nicoletti,
Samar Dissoki,
Paola Paterini,
Pier Poalo Piccaluga,
Filippo Lodi,
Pier-Luigi Lollini,
Stefano Fanti,
Guido Biasco
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ABSTRACT: The in vivo evaluation of three modified polyethylene glycol (PEG)-anilinoquinazoline derivatives labeled with (124)I, (18)F, and (11)C as potential positron emission tomography (PET) bioprobes for visualizing epidermal growth factor receptor (EGFR) in cancer using small animal PET.
Xenograft mice with the human glioblastoma cell lines U138MG (lacking EGFR expression) and U87MG.wtEGFR (transfected with an overexpressing human wild-type EGFR gene) were used. Static and dynamic PET imaging was conducted for all three PEGylated compounds. Tumor necrosis, microvessel density, and EGFR levels were evaluated by histopathology and enzyme-linked immunosorbent assay.
Nineteen animal models were generated (two U138MG, three U87MG, 14 with both U138MG and U87MG bilateral masses). In static images, a slight increase in tracer uptake was observed in tumors, but in general, there was no retention of tracer uptake over time and no difference in uptake between U138MG and U87MG masses. In addition, no significant uptake was demonstrated in dynamic scans of the (18)F-PEG tracer. No necrosis was present except in four animals. MVD was 9.6 and 48 microvessels/×400 field in the U138GM and U87GM masses, respectively (p = 0.00008). Similarly, the microvessel grades were generally higher in the U87GM group (p = 0.002). Total EGFR amount was higher in U87MG than U138MG masses (p = 0.001), but the ratio of activated (pY1068) to total EGFR did not differ (p = 0.95).
PEGylated tracers labeled with (11)C, (124)I, and (18)F showed no significant difference in uptake between U138MG and U87MG glioblastoma xenograft mice. The tracer binding with EGFR could be influenced by activation of the tyrosine kinase portion of the receptor which was similar in U138MG and U87MG. Despite these results, these tracers should be investigated in animal models with mutant EGFR genes to determine whether aberrant receptor function plays a role in tumor uptake.
Molecular imaging and biology: MIB: the official publication of the Academy of Molecular Imaging 04/2010; 12(6):616-25. · 2.47 Impact Factor
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ABSTRACT: In a continued effort to find a suitable PET tracer for visualization of angiogenic processes, we explored the 3,4-diarylmaleimide family, known to have high affinity and selectivity towards the VEGFR-TKs. One previously reported agent and three new halogen-containing 3,4-diarylmaleimide derivatives were synthesized. The four maleimide derivatives were evaluated for their affinity and selectivity towards the VEGFRs and exhibited promising results. An automated carbon-11 radiolabeling route with a total synthesis time of 50min successfully labeled the lead compound, resulting in 1.55+/-0.15GBq of tracer with a radiochemical yield of 20+/-2%, 96% radiochemical purity and a SA of 111+/-22GBq/micromol (EOB, n=5). The tracer possessed high stability in in vitro blood stability tests and specific VEGFR-TK binding profiles in intact cell binding experiments. Tracer lipophilicity was evaluated in an n-octanol/phosphate buffer system giving a LogD(7.4) of 1.99+/-0.04. For the in vivo experiments, two animal models were used. The first was a U87 glioma tumor model, frequently reported in the literature and the second, a newly developed 293/KDR tumor model. Both models were validated for VEGFR-2 expression and used in in vivo biodistribution studies. These studies revealed low accumulation and rapid washout of the tracer from tumor tissue. High accumulation of activity in the liver prompted us to examine the tracer's in vitro stability to liver microsomes, revealing low resistance to P450 metabolism. In spite of encouraging in vitro results, the labeled lead tracer failed to accumulate in VEGFR-2 overexpressing tumors. It is possible that poor resistance to P450 metabolism reduces tracer's circulation leading to low tumor accumulation.
Bioorganic & medicinal chemistry 01/2010; 18(2):612-20. · 2.82 Impact Factor
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ABSTRACT: A wealth of research has focused on developing targeted cancer therapies by specifically inhibiting epidermal growth factor receptor tyrosine kinase (EGFR-TK). However, the outcome of most EGFR-TK-targeted drugs that were approved by the Food and Drug Administration or entered clinical trials has been only moderate. Enhancement of EGFR-targeted therapy hinges on a reliable in vivo quantitative molecular imaging method. Such a method would enable monitoring of receptor drug binding and receptor occupancy in vivo; determination of the duration of EGFR inhibition in vivo; and, potentially, identification of a primary or secondary mutation in EGFR leading to drug interaction or loss of EGFR recognition by the drug. This review analyzes the most recent strategies to visualize and quantify EGFR-TK in cancer by nuclear medicine imaging and describes future directions.
Journal of Nuclear Medicine 09/2009; 50(8):1199-202. · 6.38 Impact Factor
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ABSTRACT: Mice, whose ribosomal protein S6 cannot be phosphorylated due to replacement of all five phosphorylatable serine residues by alanines (rpS6(P-/-)), are viable and fertile. However, phenotypic characterization of these mice and embryo fibroblasts derived from them, has established the role of these modifications in the regulation of the size of several cell types, as well as pancreatic beta-cell function and glucose homeostasis. A relatively passive behavior of these mice has raised the possibility that they suffer from muscle weakness, which has, indeed, been confirmed by a variety of physical performance tests.
A large variety of experimental methodologies, including morphometric measurements of histological preparations, high throughput proteomic analysis, positron emission tomography (PET) and numerous biochemical assays, were used in an attempt to establish the mechanism underlying the relative weakness of rpS6(P-/-) muscles. Collectively, these experiments have demonstrated that the physical inferiority appears to result from two defects: a) a decrease in total muscle mass that reflects impaired growth, rather than aberrant differentiation of myofibers, as well as a diminished abundance of contractile proteins; and b) a reduced content of ATP and phosphocreatine, two readily available energy sources. The abundance of three mitochondrial proteins has been shown to diminish in the knockin mouse. However, the apparent energy deficiency in this genotype does not result from a lower mitochondrial mass or compromised activity of enzymes of the oxidative phosphorylation, nor does it reflect a decline in insulin-dependent glucose uptake, or diminution in storage of glycogen or triacylglycerol (TG) in the muscle.
This study establishes rpS6 phosphorylation as a determinant of muscle strength through its role in regulation of myofiber growth and energy content. Interestingly, a similar role has been assigned for ribosomal protein S6 kinase 1, even though it regulates myoblast growth in an rpS6 phosphorylation-independent fashion.
PLoS ONE 02/2009; 4(5):e5618. · 4.09 Impact Factor
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Journal of Labelled Compounds 01/2009; 52(5):151 - 157.
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Journal of Labelled Compounds 12/2008; 52(2):41 - 52.
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ABSTRACT: The dimethylamine functional group is a common component of the chemical structure of numerous drugs. The most commonly used synthetic route for carbon-11 labeled radiopharmaceuticals which contain the dimethylamine group is via C-11 methylation of the monomethyl amine precursors. Here we describe the radiosynthesis of [11C]dimethylamine (1) and its application in the direct labeling of several positron emission tomography (PET) imaging agents by-passing the preparation of the monomethyl amine precursors.
Applied Radiation and Isotopes 03/2008; 66(2):188-93. · 1.17 Impact Factor
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ABSTRACT: Protein tyrosine kinases (PTKs) play a pivotal role in signal transduction pathways and in the development and maintenance of various cancers. They are involved in multiple processes such as transcription, cell cycle progression, proliferation, angiogenesis and inhibition of apoptosis. Among the PTKs, the EGFR is one of the most widely studied and has emerged as a promising key target for the treatment of cancer. Indeed, several drugs directed at this receptor are FDA-approved and many others are at various stages of development. However, thus far, the therapeutic outcome of EGFR-targeted therapy is suboptimal and needs to be refined. Quantitative PET molecular imaging coupled with selective labelled biomarkers may facilitate in vivo EGFR-targeted drug efficacy by noninvasively assessing the expression of EGFR in tumor, guiding dose and regime by measuring target drug binding and receptor occupancy as well as potentially detecting the existence of a primary or secondary mutation leading to either drug interaction or failure of EGFR recognition by the drug. This review describes the attempts to develop labelled EGFR molecular imaging agents that are based either on low molecular weight tyrosine kinase inhibitors or monoclonal antibodies directed to the extracellular binding domain of the receptor to be used in nuclear medicine modalities.
Current pharmaceutical design 02/2008; 14(28):2983-98. · 4.41 Impact Factor
