Melinda Wuest

University of Alberta, Edmonton, Alberta, Canada

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Publications (22)54.64 Total impact

  • [Show abstract] [Hide abstract]
    ABSTRACT: Objective The objective of the study is to demonstrate the feasibility of using [11C]-choline positron-emission tomography (PET)/CT to deliver helical tomotherapy (HT) to the prostate with a simultaneous integrated boost to dominant intraprostatic lesions as a biological target volume for dose escalation. Methods Eleven patients with intermediate-risk prostate cancer were included in this virtual planning study. Pretreatment baseline [11C]-choline PET/CT scans were acquired with a PET/CT scanner dynamically in 2-min frames from injection to 40 min post injection. PET data was reconstructed using the RAMLA 3D algorithm and analyzed to identify dominant intraprostatic lesion(s). Dominant lesions were defined as biological target volume(s) (BTV) including all voxels with a standardized uptake value of 75 % or above relative to the maximum standard uptake value (SUV) within the prostate gland. Three target volumes for optimization included the following: PTV78 (BTV + 5 mm margin), PTV68 (prostate + 5 mm posteriorly and 10 mm in all other dimensions), and PTV50 (prostate gland and proximal seminal vesicles + 7 mm margin posteriorly and 10 mm in all other dimensions). Dose constraints on organs at risk were implemented based on a published data using hypofractionated IMRT with long-term follow-up. Helical tomotherapy plans were generated to deliver hypofractionated radiation therapy to these volumes using simultaneous integrated boost in 25 fractions. Results Eight patients had one identifiable contiguous BTV, and the other three patients had two noncontiguous BTVs. The mean BTV ratio to prostate volume ratio was 6.03 % (minimum 0.80 %, maximum 13.44 %). Target volume and normal tissue constraints were met in seven of the 11 patients enrolled in the study. Targets and structures in the four patients that did not meet constraints were the bladder (3 patients), peritoneal cavity (2 patients), rectum (1 patient), PTV68 (1 patient), and PTV50 (1 patient). Conclusion It is feasible in selected patients to use [11C]-choline PET/CT to deliver hypofractionated dose-escalated helical tomotherapy to dominant intraprostatic lesions with simultaneous integrated boost using clinically established normal tissue constraints.
    Journal of Radiation Oncology. 12/2014;
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    ABSTRACT: Introduction 18 F-labeled amino acids are important PET radiotracers for molecular imaging of cancer. This study describes synthesis and radiopharmacological evaluation of 2-amino-5-(4-[18 F]fluorophenyl)pent-4-ynoic acid ([18 F]FPhPA) as a novel amino acid radiotracer for oncologic imaging. Methods 18 F]FPhPA was prepared using Pd-mediated Sonogashira cross-coupling reaction between 4-[18 F]fluoroiodobenzene ([18 F]FIB) and propargylglycine. The radiopharmacological profile of [18 F]FPhPA was evaluated in comparison with O-(2-[18 F]fluoroethyl)-L-tyrosine ([18 F]FET) using the murine breast cancer cell line EMT6 involving cellular uptake studies, radiotracer uptake competitive inhibition experiments and small animal PET imaging. Results 18 F]FPhPA was prepared in 42 ± 10% decay-corrected radiochemical yield with high radiochemical purity > 95% after semi-preparative HPLC purification. Cellular uptake of L-[18 F]FPhPA reached a maximum of 58 ± 14 % radioactivity/mg protein at 90 min. Lower uptake was observed for racemic and D-[18 F]FPhPA Radiotracer uptake inhibition studies by synthetic and naturally occurring amino acids suggested that Na+-dependent system ASC, especially ASCT2, and Na+-independent system L are important amino acid transporters for [18 F]FPhPA uptake into EMT6 cells. Small animal PET studies demonstrated similar high tumor uptake of [18 F]FPhPA in EMT6 tumor-bearing mice compared to [18 F]FET reaching a maximum standardized uptake value (SUV) of 1.35 after 60 min p.i.. Muscle uptake of [18 F]FPhPA was higher (SUV30min = 0.65) compared to [18 F]FET (SUV30min = 0.40), whereas [18 F]FPhPA showed a more rapid uptake and clearance from the brain compared to [18 F]FET. Conclusion L-[18 F]FPhPA is the first 18 F-labeled amino acid prepared through Pd-mediated cross-coupling reaction. Advances in Knowledge and Implications for patient Care L-[18 F]FPhPA displayed promising properties as a novel amino acid radiotracer for molecular imaging of system ASC and system L amino acid transporters in cancer.
    Nuclear Medicine and Biology 09/2014; · 2.52 Impact Factor
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    ABSTRACT: The radiosynthesis and radiopharmacological evaluation including small animal PET imaging of a novel 64Cu-labelled cryptand molecule ([64Cu]CryptTM) possessing a tris-pyridyl/tris-amido set of donor atoms is described.
    Medicinal Chemistry Communication 05/2014; 5:958-962. · 2.72 Impact Factor
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    ABSTRACT: 6-Deoxy-6-[(18)F]fluoro-D-fructose (6-[(18)F]FDF) is a promising PET radiotracer for imaging GLUT5 in breast cancer. The present work describes GMP synthesis of 6-[(18)F]FDF in an automated synthesis unit (ASU) and dosimetry calculations to determine radiation doses in humans. GMP synthesis and dosimetry calculations are important prerequisites for first-in-human clinical studies of 6-[(18)F]FDF. The radiochemical synthesis of 6-[(18)F]FDF was optimized and adapted to an automated synthesis process using a Tracerlab FXFN ASU (GE Healthcare). Starting from 30 GBq of cyclotron-produced n.c.a. [(18)F]fluoride, 2.9 ± 0.1 GBq of 6-[(18)F]FDF could be prepared within 50 min including HPLC purification resulting in an overall decay-corrected radiochemical yield of 14 ± 3% (n = 11). Radiochemical purity exceeded 95%, and the specific activity was greater than 5.1 GBq/μmol. Sprague-Dawley rats were used for biodistribution experiments, and dynamic and static small animal PET experiments. Biodistribution studies served as basis for allometric extrapolation to the standard man anatomic model and normal organ-absorbed dose calculations using OLINDA/EXM software. The calculated human effective dose for 6-[(18)F]FDF was 0.0089 mSv/MBq. Highest organ doses with a dose equivalent of 0.0315 mSv/MBq in a humans were found in bone. Injection of 370 MBq (10 mCi) of 6-[(18)F]FDF results in an effective whole body radiation dose of 3.3 mSv in humans, a value comparable to that of other (18)F-labeled PET radiopharmaceuticals. The optimized automated synthesis under GMP conditions, the good radiochemical yield and the favorable human radiation dosimetry estimates support application of 6-[(18)F]FDF in clinical trials for molecular imaging of GLUT5 in breast cancer patients.
    American Journal of Nuclear Medicine and Molecular Imaging 01/2014; 4(3):248-59. · 3.25 Impact Factor
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    ABSTRACT: Cyclooxygenase (COX) is the key enzyme within the complex conversion of arachidonic acid into prostaglandins (PGs). Inhibitors of this enzyme represent a particularly promising class of compounds for chemoprevention and cancer therapy. The experimental data on the involvement of COX isoform COX-2 in tumour development and progression, as well as the observed overexpression of COX-2 in a variety of human cancers provide the rationale for targeting COX-2 for molecular imaging and therapy of cancer. A series of trifluoromethyl-substituted pyrimidines was prepared as a novel class of selective COX-2 inhibitors, based on the lead structure . All compounds were tested in cyclooxygenase (COX) assays in vitro to determine COX-1 and COX-2 inhibitory potency and selectivity. Molecular docking studies using the catalytic site of COX-1 and COX-2, respectively, provided complementary theoretical support for the obtained experimental biological structure-activity relationship data of three highly potent and selective fluorobenzyl-containing COX-2 inhibitors. Selected fluorobenzyl-substituted pyrimidine derivatives were further developed as (18)F-labelled radiotracers ([(18)F], [(18)F], [(18)F]). Radiotracers [(18)F] and [(18)F] were radiolabelled using 4-[(18)F]fluorobenzylamine ([(18)F]FBA) as a building block. Radiotracer [(18)F] was radiofluorinated directly using a nucleophilic aromatic substitution reaction with no-carrier-added (n.c.a.) [(18)F]fluoride on an iodylaryl compound as a labelling precursor.
    Organic & Biomolecular Chemistry 10/2013; · 3.57 Impact Factor
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    ABSTRACT: Cyclooxygenase (COX) enzyme is responsible for the formation of important biological mediators including prostaglandins, prostacyclin and thromboxane to trigger many physiological and patho-physiological responses. COXs exist in two distinct isoforms, a constitutively expressed form (COX-1) and an inducible form (COX-2). COX-2 is involved in the body's response to inflammation and pain. Moreover, it has also been shown that COX-2 is overexpressed in many human cancers, and that COX-2 is involved in various neurodegenerative diseases such as Parkinson's and Alzheimer's disease. COX-2 inhibitors are among the most widely used therapeutics for the treatment of chronic and acute pain and inflammation. Non-invasive monitoring of COX-2 functional expression by means of nuclear molecular imaging techniques like positron emission tomography (PET) and single photon emission computed tomography (SPECT) might provide unique opportunities to obtain data on COX-2 expression levels during disease manifestation and progression to study potential roles of COX-2 under various pathological conditions. The present review summarizes recent research efforts directed to the design and synthesis of radiotracers as molecular probes with special emphasis on COX-2 imaging.
    Current Medicinal Chemistry 09/2013; · 3.72 Impact Factor
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    ABSTRACT: Bombesin (BBN) and BBN analogues have attracted much attention as high-affinity ligands for selective targeting of the gastrin-releasing peptide (GRP) receptor. GRP receptors are overexpressed in a variety of human cancers including prostate cancer. Radiolabeled BBN derivatives are promising diagnostic probes for molecular imaging of GRP receptor-expressing prostate cancer. This study describes the synthesis and radiopharmacological evaluation of various metabolically stabilized fluorobenzoylated bombesin analogues (BBN-1, BBN-2, BBN-3). Three fluorobenzoylated BBN analogues containing an aminovaleric (BBN-1, BBN-2), or an aminooctanoic acid linker (BBN-3) were tested in a competitive binding assay against (125)I-[Tyr(4)]-BBN for their binding potency to the GRP receptor. Intracellular calcium release in human prostate cancer cells (PC3) was measured to determine agonistic or antagonistic profiles of fluorobenzoylated BBN derivatives. Bombesin derivative BBN-2 displayed the highest inhibitory potency toward GRP receptor (IC50=8.7±2.2nM) and was subsequently selected for radiolabeling with fluorine-18 ((18)F) through acylation with N-succinimidyl-4-[(18)F]fluorobenzoate ([(18)F]SFB). The radiopharmacological profile of (18)F-labeled bombesin [(18)F]BBN-2 was evaluated in PC3 tumor-bearing NMRI nude mice involving metabolic stability studies, biodistribution experiments and dynamic small-animal PET studies. All fluorobenzoylated BBN derivatives displayed high inhibitory potency toward the GRP receptor (IC50=8.7-16.7nM), and all compounds exhibited antagonistic profiles as determined in an intracellular calcium release assay. The (18)F-labeled BBN analogue [(18)F]BBN-2 was obtained in 30% decay-corrected radiochemical yield with high radiochemical purity >95% after semi-preparative HPLC purification. [(18)F]BBN-2 showed high metabolic stability in vivo with 65% of the radiolabeled peptide remaining intact after 60min p.i. in mouse plasma. Biodistribution experiments and dynamic small-animal PET studies demonstrated high tumor uptake of [(18)F]BBN-2 in PC3 xenografts (2.75±1.82 %ID/g after 5min and 2.45±1.25 %ID/g after 60min p.i.). Specificity of radiotracer uptake in PC3 tumors was confirmed by blocking experiments. The present study demonstrates that (18)F-labeled BBN analogue [(18)F]BBN-2 is a suitable PET radiotracer with favorable metabolic stability in vivo for molecular imaging of GRP receptor-positive prostate cancer.
    Nuclear Medicine and Biology 08/2013; · 2.52 Impact Factor
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    ABSTRACT: The radiometal (64)Cu is now widely used in the development of diagnostic imaging agents for positron emission tomography (PET). The present study has led to the development and evaluation of a novel chelating agent for (64)Cu: the new monothiourea tripodal ligand 1-benzoyl-3-{6-[(bis-pyridin-2-ylmethyl-amino)-methyl]-pyridin-2-yl}-thiourea (MTUBo). X-ray crystallographic analysis has shown this ligand forms a mononuclear complex with copper(ii) and co-ordinates via a trigonal bipyramidal N4S array of donor atoms. Promisingly, cell uptake studies revealed that (64)Cu-MTUBo selectively accumulates in EMT-6 cells incubated under hypoxic conditions which may result from its relatively high Cu(II/I) redox potential. Small-animal PET imaging and ex vivo biodistribution studies in EMT-6 tumor bearing BALB/c mice revealed significant tumor uptake after 1 h p.i., yielding tumor-to-muscle (T/M) and tumor-to-blood (T/B) ratios of 8.1 and 1.1, respectively. However, injection of (64)Cu-acetate resulted in similar uptake indicating that the observed uptake was most likely non-specific. Despite showing high in vitro stability, it is likely that in vivo the complex undergoes transchelation to proteins within the blood in a relatively short timeframe. For comparison, the hypoxia imaging agent (64)Cu-ATSM was also evaluated in the same murine tumor model and showed about 60% higher tumor uptake than (64)Cu-MTUBo.
    Dalton Transactions 07/2013; · 4.10 Impact Factor
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    ABSTRACT: The copper-free click chemistry reaction between norbornene and tetrazine species is known to proceed in a rapid, reliable and selective manner under mild conditions. Due to these attractive properties, this reaction has recently been explored as a generally applicable method of bioconjugation. Here, we report a convenient synthetic procedure towards a novel (18)F-labelled norbornene derivative () and have evaluated its ability to undergo strain-promoted copper-free click chemistry reactions with two model tetrazine species: an asymmetric dipyridyl tetrazine derivative (Tz) and a tetrazine thiourea-coupled stabilised bombesin peptide (TT-BBN). In both cases, was found to undergo rapid and high-yielding click chemistry reactions. Furthermore, as reactions of this type could also potentially be used in vivo to facilitate the development of a novel pretargeting approach for tumour imaging and therapy, we have also assessed the radiopharmacological profile (bioavailability, biodistribution, blood clearance and metabolic stability) of in normal BALB/c mice. This radiolabelled compound exhibits both high bioavailability and metabolic stability with approximately 90% remaining intact up to 30 min following administration.
    Organic & Biomolecular Chemistry 05/2013; · 3.57 Impact Factor
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    ABSTRACT: The objective of the present study was to analyze, with relatively high sensitivity and specificity, uptake properties of [(11)C]-choline in prostate cancer patients by means of positron-emission tomography (pet)/computed tomography (ct) imaging using objectively defined pet parameters to test for statistically significant changes before, during, and after external-beam radiation therapy (ebrt) and to identify the time points at which the changes occur. The study enrolled 11 patients with intermediate-risk prostate cancer treated with ebrt, who were followed for up to 12 months after ebrt. The [(11)C]-choline pet scans were performed before treatment (baseline); at weeks 4 and 8 of ebrt; and at 1, 2, 3, 6, and 12 months after ebrt. Analysis of [(11)C]-choline uptake in prostate tissue before treatment resulted in a maximum standardized uptake value (suvmax) of 4.0 ± 0.4 (n = 11) at 40 minutes after injection. During week 8 of ebrt, the suvmax declined to 2.9 ± 0.1 (n = 10, p < 0.05). At 2 and 12 months after ebrt, suvmax values were 2.3 ± 0.3 (n = 10, p < 0.01) and 2.2 ± 0.2 (n = 11, p < 0.001) respectively, indicating that, after ebrt, maximum radiotracer uptake in the prostate was significantly reduced. Similar effects were observed when analyzing the tumour:muscle ratio (tmr). The tmr declined from 7.4 ± 0.6 (n = 11) before ebrt to 6.1 ± 0.4 (n = 11, nonsignificant) during week 8 of ebrt, to 5.6 ± 0.03 (n = 11, p < 0.05) at 2 months after ebrt, and to 4.4 ± 0.4 (n = 11, p < 0.001) at 12 months after ebrt. Our study demonstrated that intraprostatic [(11)C]-choline uptake in the 11 analyzed prostate cancer patients significantly declined during and after ebrt. The pet parameters SUVmax and tmr also declined significantly. These effects can be detected during radiation therapy and up to 1 year after therapy. The prognostic value of these early and statistically significant changes in intraprostatic [(11)C]-choline pet avidity during and after ebrt are not yet established. Future studies are indicated to correlate changes in [(11)C]-choline uptake parameters with long-term biochemical recurrence to further evaluate [(11)C]-choline pet changes as a possible, but currently unproven, biomarker of response.
    Current Oncology 04/2013; 20(2):104-10. · 1.63 Impact Factor
  • Melinda Wuest, Frank Wuest
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    ABSTRACT: Localized hypoxia, the physiological hallmark of many clinical pathologies, is the consequence of acute or chronic ischemia in the affected region or tissue. The versatility, sensitivity, quantitative nature, and increasing availability of positron emission tomography (PET) make it the preclinical and clinical method of choice for functional imaging of tissue hypoxia at the molecular level. The progress and current status of radiotracers for hypoxia-specific PET imaging are reviewed in this article including references mainly focused on radiochemistry and also relevant to molecular imaging of hypoxia in preclinical and clinical studies.
    Journal of Labelled Compounds 03/2013; 56(3-4):244-250.
  • JOURNAL OF LABELLED COMPOUNDS & RADIOPHARMACEUTICALS; 01/2013
  • JOURNAL OF LABELLED COMPOUNDS & RADIOPHARMACEUTICALS; 01/2013
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    ABSTRACT: Phosphopeptides represent interesting compounds to study and elucidate cellular protein phosphorylation/dephosphorylation processes underlying various signal transduction pathways. However, studies of phosphopeptide action in cells are severely constrained by the negatively charged phosphate moiety of the phosphopeptide resulting in poor transport through the cell membrane. The following study describes the synthesis and radiopharmacological evaluation of two (18)F-labeled phosphopeptide-cell-penetrating peptide dimers. The polo-like kinase-1-binding hexaphosphopeptide H-Met-Gln-Ser-pThr-Pro-Leu-OH was coupled to cell-penetrating peptides (CPPs), either sC18, a cathelicidin-derived peptide, or the human calcitonin derivative hCT(18-32)-k7. Radiolabeling was accomplished with the prosthetic group N-succinimidyl 4-[(18)F]fluorobenzoate ([(18)F]SFB) using both, conventional and microfluidic-based bioconjugation of [(18)F]SFB to N-terminal end of phosphopeptide part of the peptide dimers. Cellular uptake studies in human cancer cell lines HT-29 and FaDu cells at 4 °C and 37 °C and small animal PET in BALB/c mice were utilized for radiopharmacological characterization. Isolated radiochemical yields ranged from 2% to 4% for conventional bioconjugation with [(18)F]SFB. Significantly improved isolated radiochemical yields of up to 26% were achieved using microfluidic technology. Cellular uptake studies of radiolabeled phosphopeptide and phosphopeptide-CPP dimers indicate enhanced internalization of 50% ID/mg protein after 2 h for both phosphopeptide dimers compared to the phosphopeptide alone (<1% ID/mg protein). In vivo biodistribution of (18)F-labeled peptide dimers was determined with small animal PET revealing a superior biodistribution pattern of sC18-containing peptide dimer MQSpTPL-sC18 [(18)F]4. ([18)F]SFB labeling of the phosphopeptide-CPP dimers using a microfluidic system leads to an improved chemoselectivity towards the N-terminal NH(2) group compared to the conventional labeling approach. Cell-penetrating peptide sC18 can be considered as an ideal molecular shuttle for intracellular delivery of the Plk1-PBD-binding hexaphosphopeptide as demonstrated by its favourable radiopharmacological profile.
    Nuclear Medicine and Biology 07/2012; 39(8):1202-12. · 2.52 Impact Factor
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    ABSTRACT: Abstract Several F-18-labeled 2-nitroimidazole (azomycin) derivatives have been proposed for imaging hypoxia using positron emission tomography (PET). Their cell penetration is based on passive diffusion, which limits their intracellular concentration maxima. The purpose of this study was to investigate the uptake of N-(2-[(18)F]fluoro-3-(6-O-glucosyl)propyl-azomycin ([(18)F]F-GAZ), a new azomycin-glucose conjugate, in vitro and in vivo. [(18)F]F-GAZ was synthesized from its tetraacetyl nosylate precursor by nucleophilic radiofluorination. [(18)F]F-GAZ was evaluated in vivo in EMT-6 tumor-bearing Balb/C mice utilizing the PET and biodistribution analysis. In vitro uptake of [(18)F]FDG by EMT-6 cells was measured in the presence of unlabeled F-GAZ, 2-FDG, and D-glucose. [(18)F]F-GAZ was rapidly cleared from all tissues, including the blood pool and kidneys, with ultimate accumulation in the urinary bladder. Uptake of tracer doses of [(18)F]F-GAZ into EMT-6 tumors was fast, reaching a standardized uptake value of 0.66±0.05 within 5-6 minutes postinjection (p.i.), and decreased to 0.24±0.04 by 60 minutes p.i. (n=6). A tumor-muscle ratio of 1.87±0.18 was observed after 60 minutes. Total uptake of [(18)F]F-GAZ in tumors (60 minutes) amounted to 1.25%±0.15% ID/g versus 0.61%±0.14% ID/g (n=4) in muscle. Similar biodistribution and excretion were observed using carrier-added (100 mg/kg) doses of F-GAZ. In vitro, D-glucose and unlabeled 2-FDG were two orders of magnitude more potent than F-GAZ as competitive inhibitors of [(18)F]FDG uptake into EMT-6 cells. Besides its interaction with glucose transporters, F-GAZ seems to be not transported in the presence of glucose. Furthermore, [(18)F]F-GAZ is unlikely to be effective as a hypoxia imaging agent. The low in vivo toxicity and substantial retention in tumor observed at high doses of F-GAZ do provide rationale for further testing as a radiosensitizer for external beam radiation therapy of radioresistant, hypoxic tumors.
    Cancer Biotherapy & Radiopharmaceuticals 06/2012; 27(8):473-80. · 1.44 Impact Factor
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    ABSTRACT: A new synthesis of O-(2-[(18)F]fluoroethyl)-L-tyrosine [(18)F]FET was developed using a NanoTek® microfluidic synthesis system (Advion BioSciences, Inc.). Optimal reaction conditions were studied through screening different reaction parameters like temperature, flow rate, reaction time, concentration of the labeling precursor, and the applied volume ratio between the labeling precursor and [(18)F]fluoride. [(18)F]FET was obtained after HPLC purification with 50% decay-corrected radiochemical yield starting from as little as 40 μg of labeling precursor. Small animal PET studies in EMT-6 tumor bearing mice showed radioactivity accumulation in the tumor (SUV(60min) 1.21±0.2) resulting in an slightly increasing tumor-to-muscle ratio over time.
    Bioorganic & medicinal chemistry letters 03/2012; 22(6):2291-5. · 2.65 Impact Factor
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    ABSTRACT: A series of fluorobenzoylated di- and tripeptides as potential leads for the development of molecular probes for imaging of COX-2 expression was prepared according to standard Fmoc-based solid-phase peptide synthesis. All peptides were assessed for their COX-2 inhibitory potency and selectivity profile in a fluorescence-based COX binding assay. Within the series of 15 peptides tested, cysteine-containing peptides numbered 7, 8, 11 and 12, respectively, were the most potent COX-2 inhibitors possessing IC(50) values ranging from 5 to 85 μM. Fluorobenzoylated tripeptides 7 and 8 displayed some COX-2 selectivity (COX-2 selectivity index 2.1 and 1.6), whereas fluorobenzoylated dipeptides 11 and 12 were shown not to be COX-2 selective. Fluorbenzoylated tripeptide FB-Phe-Cys-Ser-OH was further used in molecular modeling docking studies to determine the binding mode within the active site of the COX-2 enzyme.
    Bioorganic & medicinal chemistry 02/2012; 20(7):2221-6. · 2.82 Impact Factor
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    ABSTRACT: Positron emission tomography (PET) allows detection of functional changes in malignant tissue. Establishment of an immortalized immunocompetent breast cancer mouse model would provide a useful platform for the analysis of novel cancer treatment strategies. This study describes a comparative functional evaluation of murine breast cancer models established from polyoma virus middle T antigen (PyMT)-derived tumors using small animal PET imaging with [(18)F]FDG and [(18)F]FLT. Primary PyMT tumor-derived cells and a cell line derived from these tumors (MTHJ) were injected subcutaneously into immunocompetent FVB mice to generate breast cancer xenografts. Tumor growth rates were comparable in both models and tumors were analyzed after 4-5 weeks post-injection. [(18)F]FDG uptake in vitro followed a comparable trend in both models but reached higher uptake levels in primary PyMT cells vs. MTHJ cells after 120 min. At all time points, [(18)F]FLT uptake was significantly higher in MTHJ compared to primary PyMT cells. Dynamic small animal PET imaging with [(18)F]FDG revealed standardized uptake values (SUVs) of 2.5±0.1 (n=8) in tumors from primary cells and 2.8±0.4 (n=6) in MTHJ tumors after 60 min p.i.. The corresponding tumor-muscle-ratios were 9.3±1.5 and 10.4±0.9, respectively. Uptake of [(18)F]FLT resulted in slightly higher SUV(60min) in MTHJ tumors (1.1±0.1, n=6) compared to tumors from primary cells (SUV(60min)=0.9±0.05, n=8, p=0.07). The tumor-muscle-ratio was comparable in both tumors (2.1±0.2 and 1.8±0.1, respectively). The PET imaging data demonstrates that the functional profile of immunocompetent murine breast tumor model MTHJ remains the same as in primary-derived PyMT tumors in vivo. Metabolic and proliferative rates as assessed with [(18)F]FDG and [(18)F]FLT are comparable in both tumor models. The observed high SUV(60min) of 2.8±0.4 with [(18)F]FDG in MTHJ tumors allows one to monitor efficacy of therapeutic interventions connected with changes in metabolic response of the tumor by means of small animal PET.
    American Journal of Nuclear Medicine and Molecular Imaging 01/2012; 2(1):88-98. · 3.25 Impact Factor
  • Vincent Bouvet, Melinda Wuest, Frank Wuest
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    ABSTRACT: The copper-free strain-promoted click chemistry between (18)F-labeled aza-dibenzocyclooctyne [(18)F]FB-DBCO and various azides is described. [(18)F]FB-DBCO was prepared in 85% isolated radiochemical yield (decay-corrected) through acylation of amino aza-dibenzocyclooctyne 1 with N-succinimidyl 4-[(18)F]fluorobenzoate ([(18)F]SFB). [(18)F]FB-DBCO showed promising radiopharmacological profil with fast blood clearance as assessed with dynamic small animal PET studies. Metabolic stability of [(18)F]FB-DBCO was 60% of intact compound after 60 min post injection in normal Balb/C mice and blood clearance half-life was determined to be 53 s based on the time-activity-curve (TAC). Copper-free click chemistry was performed with various azides at low concentrations (1-2 μM) which differed in their structural complexity in different solvents (methanol, water, phosphate buffer and in bovine serum albumin (BSA) solution). Reaction proceeded best in methanol (>95% yield after 15 min at room temperature), whereas reaction in BSA required longer reaction times of 60 min and 40 °C upon completion.
    Organic & Biomolecular Chemistry 09/2011; 9(21):7393-9. · 3.57 Impact Factor
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    ABSTRACT: Several clinical studies have shown low or no expression of GLUT1 in breast cancer patients, which may account for the low clinical specificity and sensitivity of 2-deoxy-2-[(18)F]fluoro-D-glucose ([(18)F]FDG) used in positron emission tomography (PET). Therefore, it has been proposed that other tumor characteristics such as the high expression of GLUT2 and GLUT5 in many breast tumors could be used to develop alternative strategies to detect breast cancer. Here we have studied the in vitro and in vivo radiopharmacological profile of 6-deoxy-6-[(18)F]fluoro-D-fructose (6-[(18)F]FDF) as a potential PET radiotracer to image GLUT5 expression in breast cancers. Uptake of 6-[(18)F]FDF was studied in murine EMT-6 and human MCF-7 breast cancer cells over 60 min and compared to [(18)F]FDG. Biodistribution of 6-[(18)F]FDF was determined in BALB/c mice. Tumor uptake was studied with dynamic small animal PET in EMT-6 tumor-bearing BALB/c mice and human xenograft MCF-7 tumor-bearing NIH-III mice in comparison to [(18)F]FDG. 6-[(18)F]FDF metabolism was investigated in mouse blood and urine. 6-[(18)F]FDF is taken up by EMT-6 and MCF-7 breast tumor cells independent of extracellular glucose levels but dependent on the extracellular concentration of fructose. After 60 min, 30±4% (n=9) and 12±1% (n=7) ID/mg protein 6-[(18)F]FDF was found in EMT-6 and MCF-7 cells, respectively. 6-deoxy-6-fluoro-d-fructose had a 10-fold higher potency than fructose to inhibit 6-[(18)F]FDF uptake into EMT-6 cells. Biodistribution in normal mice revealed radioactivity uptake in bone and brain. Radioactivity was accumulated in EMT-6 tumors reaching 3.65±0.30% ID/g (n=3) at 5 min post injection and decreasing to 1.75±0.03% ID/g (n=3) at 120 min post injection. Dynamic small animal PET showed significantly lower radioactivity uptake after 15 min post injection in MCF-7 tumors [standard uptake value (SUV)=0.76±0.05; n=3] compared to EMT-6 tumors (SUV=1.23±0.09; n=3). Interestingly, [(18)F]FDG uptake was significantly different in MCF-7 tumors (SUV(15 min) 0.74±0.12 to SUV(120 min) 0.80±0.15; n=3) versus EMT-6 tumors (SUV(15 min) 1.01±0.33 to SUV(120 min) 1.80±0.25; n=3). 6-[(18)F]FDF was shown to be a substrate for recombinant human ketohexokinase, and it was metabolized rapidly in vivo. Based on the GLUT5 specific transport and phosphorylation by ketohexokinase, 6-[(18)F]FDF may represent a novel radiotracer for PET imaging of GLUT5 and ketohexokinase-expressing tumors.
    Nuclear Medicine and Biology 05/2011; 38(4):461-75. · 2.52 Impact Factor