Browsing by Author "Denoyer, D"

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    Discovery of [F-18]N-(2-(Diethylamino)ethyl)-6-fluoronicotinamide: a melanoma positron emission tomography imaging radiotracer with high tumor to body contrast ratio and rapid renal clearance
    (American Chemical Society, 2009-09-10) Greguric, I; Taylor, SR; Denoyer, D; Ballantyne, P; Berghofer, PJ; Roselt, P; Pham, TQ; Mattner, F; Bourdier, T; Neels, OC; Dorow, DS; Loc'h, C; Hicks, RJ; Katsifis, A
    The high melanoma uptake and rapid body clearance displayed by our series of [123I]iodonicotinamides prompted the development of [18F]N-(2-(diethylamino)ethyl)-6-fluoronicotinamide ([18F]2), a novel radiotracer for PET melanoma imaging. Significantly, unlike fluorobenzoates, [18F]fluorine incorporation on the nicotinamide ring is one step, facile, and high yielding. [18F]2 displayed high tumor uptake, rapid body clearance via predominantly renal excretion, and is currently being evaluated in preclinical studies for progression into clinical trials to assess the responsiveness of therapeutic agents. © 2009, American Chemical Society
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    High-contrast PET of melanoma using F-18-MEL050, a selective probe for melanin with predominantly renal clearance
    (Society of Nuclear Medicine, 2010-03) Denoyer, D; Greguric, I; Roselt, P; Neels, OC; Aide, N; Taylor, SR; Katsifis, A; Dorow, DS; Hicks, RJ
    The aim of this study was to evaluate the novel probe 18F-6-fluoro-N-[2-(diethylamino)ethyl] pyridine-3-carboxamide (18F-MEL050) for the imaging of primary and metastatic melanoma. Methods: PET using 18F-MEL050 was performed in murine models of melanoma. The specificity of 18F-MEL050 was studied by comparing its accumulation in pigmented B16-F0 allograft tumors with that of human amelanotic A375 xenografts using PET and high-resolution autoradiography. 18F-MEL050 PET results were compared with 18F-FDG PET, the current standard in melanoma molecular imaging. To test the ability of 18F-MEL050 to assess the metastatic spread of melanoma, a murine model of lung metastasis was imaged by PET/CT, and results correlated with physical assessment of tumor burden in the lungs. Results: In pigmented B16-F0 grafts, 18F-MEL050 PET yielded a tumor-to-background ratio of approximately 20:1 at 1 h and greater than 50:1 at 2 and 3 h. In the B16-F0 melanoma allograft model, tumor-to-background ratio was more than 9-fold higher for 18F-MEL050 than for 18F-FDG (50.9 ± 6.9 vs. 5.8 ± 0.5). No uptake was observed in the amelanotic melanoma xenografts. Intense uptake of 18F-MEL050 was evident in metastatic lesions in the lungs of B16-BL6 tumor–bearing mice on PET at 2 h after tracer injection, with high concordance between 18F-MEL050 accumulation on PET/CT and tumor burden determined at necroscopy. Conclusion: 18F-MEL050 has a rapid tumor uptake and high retention with specificity for melanin, suggesting great potential for noninvasive clinical evaluation of suspected metastatic melanoma. © 2010, Society of Nuclear Medicine
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    Improved detection of regional melanoma metastasis using 18F-6-Fluoro-N-[2-(Diethylamino)Ethyl] Pyridine-3-Carboxamide, a Melanin-specific PET probe, by perilesional administration
    (Society of Nuclear Medicine, 2011-01-01) Denoyer, D; Potdevin, T; Roselt, P; Neels, OC; Kirby, L; Greguric, I; Katsifis, A; Dorow, DS; Hicks, RJ
    The efficacy of differing routes of administration of 18F-6-fluoro-N-[2-(diethylamino)ethyl] pyridine-3-carboxamide (18F-MEL050), a new benzamide-based PET radiotracer for imaging regional lymph node metastasis in melanoma, was assessed. Methods: B16-Black/6 metastatic melanoma cells harboring an mCherry transgene were implanted into the left-upper-foot surface of 49 C57 Black/6 mice as a model of popliteal lymph node (PLN) metastasis. Ultrasound scanning of the left PLN was performed at baseline and in combination with 18F-MEL050 PET on days 5, 9, and 14. Mice were divided into 2 groups to compare the results of tracer administration either subcutaneously at the tumor site (local) or in the lateral tail vein (systemic). After PET on each imaging day, 5 mice per group—including any with evidence of metastasis—were sacrificed for ex vivo validation studies including assessment of retained radioactivity and presence of the mCherry transgene as a surrogate of nodal tumor burden. Results: Nine mice were judged as positive for PLN metastasis by ultrasound at day 5, and 8 PLNs were positive on 18F-MEL050 PET, 3 after systemic and 5 after local administration. Ex vivo analysis showed that ultrasound correctly identified 90% of positive PLNs, with 1 false-positive. 18F-MEL050 PET correctly identified 60% of positive PLNs after systemic administration and 100% after local administration with no false-positive results by either route. The average node-to-background ratio for positive PLNs was 6.8 in the systemic-administration group and correlated with disease burden. In the local-administration group, the mean uptake ratio was 48, without clear relation to metastatic burden. Additional sites of metastatic disease were also correctly identified by 18F-MEL050 PET. Conclusion: In addition to its potential for systemic staging, perilesional administration of 18F-MEL050 may allow sensitive and specific, noninvasive identification of regional lymph node metastasis in pigmented malignant melanomas. © 2011, Society of Nuclear Medicine
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    Preclinical characterization of 18FD-FPHCys, a new amino acid-based PET tracer
    (Springer, 2012-04-01) Denoyer, D; Kirby, L; Waldeck, K; Roselt, P; Neels, OC; Bourdier, T; Shepherd, R; Katsifis, A; Hicks, RJ
    The imaging potential of a new F-18-labelled methionine derivative, S-(3-[F-18]fluoropropyl)-d-homocysteine (F-18-D-FPHCys), and its selectivity for amino acid transporter subtypes were investigated in vitro and by imaging of human tumour xenografts. Expression of members of the system L (LAT isoforms 1-4 and 4F2hc) and ASCT (ASCT isoforms 1 and 2) amino acid transporter subclasses were assessed by quantitative real-time PCR in four human tumour models, including A431 squamous cell carcinoma, PC3 prostate cancer, and Colo 205 and HT-29 colorectal cancer lines. The first investigations for the characterization of F-18-D-FPHCys were in vitro uptake studies by comparing it with [1-C-14]-l-methionine (C-14-MET) and in vivo by PET imaging. In addition, the specific involvement of LAT1 transporters in F-18-D-FPHCys accumulation was tested by silencing LAT1 mRNA transcription with siRNAs. To determine the proliferative activity in tumour xenografts ex vivo, Ki-67 staining was used as a biomarker. A431 cells showed the highest F-18-D-FPHCys uptake in vitro and in vivo followed by Colo 205, PC3 and HT-29. A similar pattern of retention was observed with C-14-MET. F-18-D-FPHCys retention was strongly correlated with LAT1 expression both in vitro (R (2) = 0.85) and in vivo (R (2) = 0.99). Downregulation of LAT1 by siRNA inhibited F-18-D-FPHCys uptake, demonstrating a clear dependence on this transporter for tumour uptake. Furthermore, F-18-D-FPHCys accumulation mirrored cellular proliferation. The favourable properties of F-18-D-FPHCys make this tracer a promising imaging probe for detection of tumours as well as for the noninvasive evaluation and monitoring of tumour growth.© 2012, Springer.
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    Radiosynthesis and biological evaluation of L and D S-(3-[18F]Fluoropropyl)-homocysteine for tumor imaging using positron emission tomography
    (Americam Chemical Society, 2011-03-24) Bourdier, T; Shepherd, R; Berghofer, PJ; Jackson, TW; Fookes, CJR; Denoyer, D; Dorow, DS; Greguric, I; Grégoire, MC; Hicks, RJ; Katsifis, A
    Interest in radiolabeled amino acids for metabolic imaging of cancer and limitations with [11C]methionine has prompted the development of a new 18F-labeled methionine derivative S-(3-[18F]fluoropropyl)homocysteine ([18F]FPHCys). The L and D enantiomers of [18F]FPHCys were prepared from their respective protected S-(3-tosyloxypropyl)homocysteine precursors 1 by [18F]fluoride substitution using K2.2.2 and potassium oxalate, followed by acid hydrolysis on a Tracerlab FXFN synthesis module. [18F]-L-FPHCys and [18F]-D-FPHCys were isolated in 20 ( 5% radiochemical yield and >98% radiochemical and enantiomeric purity in 65 min. Competitive uptake studies in A375 and HT29 tumor cells suggest that L- and D-[18F]FPHCys are taken up by the L-transporter system. [18F]-L-FPHCys and [18F]-D-FPHCys displayed good stability In Vivo without incorporation into protein at least 2 h postinjection. Biodistribution studies demonstrate good uptake in A375 tumor-bearing rodents with tumor to blood ratios of 3.5 and 5.0 for [18F]-L-FPHCys and [18F]-D-FPHCys, respectively, at 2 h postinjection. © 2011, American Chemical Society.
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    Synthesis and in vivo evaluation of [123I]melanin-targeted agents
    (American Chemical Society, 2015-08-15) Roberts, MP; Nguyen, VH; Ashford, ME; Berghofer, PJ; Wyatt, NA; Krause-Heuer, AM; Pham, TQ; Taylor, SR; Hogan, L; Jiang, CD; Fraser, BH; Lengkeek, NA; Matesic, L; Grégoire, MC; Denoyer, D; Hicks, RJ; Katsifis, A; Greguric, I
    This study reports the synthesis, [123I]radiolabeling, and biological profile of a new series of iodinated compounds for potential translation to the corresponding [131I]radiolabeled compounds for radionuclide therapy of melanoma. Radiolabeling was achieved via standard electrophilic iododestannylation in 60–90% radiochemical yield. Preliminary SPECT imaging demonstrated high and distinct tumor uptake of all compounds, as well as high tumor-to-background ratios compared to the literature compound [123I]4 (ICF01012). The most favorable compounds ([123I]20, [123I]23, [123I]41, and [123I]53) were selected for further biological investigation. Biodistribution studies indicated that all four compounds bound to melanin containing tissue with low in vivo deiodination; [123I]20 and [123I]53 in particular displayed high and prolonged tumor uptake (13% ID/g at 48 h). [123I]53 had the most favorable overall profile of the cumulative uptake over time of radiosensitive organs. Metabolite analysis of the four radiotracers found [123I]41 and [123I]53 to be the most favorable, displaying high and prolonged amounts of intact tracer in melanin containing tissues, suggesting melanin specific binding. Results herein suggest that compound [123I]53 displays favorable in vivo pharmacokinetics and stability and hence is an ideal candidate to proceed with further preclinical [131I] therapeutic evaluation. ©2015, American Chemical Society