BRAFV600E mutation is the most frequent genetic alteration in papillary thyroid cancer (PTC). β-Catenin (Ctnnb1) is a key downstream component of canonical Wnt signaling pathway and is frequently overexpressed in PTC. BRAFV600E-driven tumors have been speculated to rely on Wnt/β-catenin signaling to sustain its growth, although many details remain to be elucidated. In this study, we investigated the role of β-catenin in BrafV600E-driven thyroid cancer in a transgenic mouse model. In BrafV600E mice with wild-type (WT) Ctnnb1 (BVE-Ctnnb1WT or BVE), overexpression of β-catenin was observed in thyroid tumors. In BrafV600E mice with Ctnnb1 knockout (BVE-Ctnnb1null), thyroid tumor growth was slowed with significant reduction in papillary architecture. This was associated with increased expression of genes involved in thyroid hormone synthesis, elevated 124iodine uptake, and serum T4. The survival of BVE-Ctnnb1null mice was increased by more than 50% during 14-month observation. Mechanistically, downregulation of MAPK, PI3K/Akt, and TGFβ pathways and loss of epithelial–mesenchymal transition (EMT) were demonstrated in the BVE-Ctnnb1null tumors. Treatment with dual β-catenin/KDM4A inhibitor PKF118–310 dramatically improved the sensitivity of BVE-Ctnnb1WT tumor cells to BRAFV600E inhibitor PLX4720, resulting in significant growth arrest and apoptosis in vitro, and tumor regression and differentiation in vivo. These findings indicate that β-catenin signaling plays an important role in thyroid cancer growth and resistance to BRAFV600E inhibitors. Simultaneously targeting both Wnt/β-catenin and MAPK signaling pathways may achieve better therapeutic outcome in BRAFV600E inhibitor-resistant and/or radioiodine-refractory thyroid cancer.

Background There is a need to develop new and more potent radiofluorinated peptide and their hybrid conjugates for multiple-receptors targeting properties that overexpress on many cancers. Methods We have synthesized MUC1-[18F] SFB and MUC1-FA-[18F] SFB hybrid conjugates using a convenient and one-step nucleophilic displacement reaction. In vitro cell binding and in vivo evaluation in animals were performed to determine the potential of these radiolabeled compounds. Results Radiochemical yields for MUC1-[18F] SFB and MUC1-FA-[18F] SFB conjugates were greater than 70% in less than 30 min synthesis time. Radiochemical purities were greater than 97% without HPLC purification, which makes these approaches amenable to automation. In vitro studies on MCF7 breast cancer cells showed that the significant amounts of the radiofluorinated conjugates were associated with cell fractions and held good affinity and specificity for MCF7 cells. In vivo characterization in Balb/c mice revealed rapid blood clearance with excretion predominantly by urinary as well as hepatobiliary systems for MUC1-[18F] SFB and MUC1-FA-[18F] SFB, respectively. Biodistribution in SCID mice bearing MCF7 xenografts, demonstrated excellent tumor uptake (12% ID/g) and favorable kinetics for MUC1-FA-[18F] SFB over MUC1-[18F]SFB. The tumor uptake was blocked by the excess co-injection of cold peptides suggesting the receptor-mediated process. Conclusion Initial PET/CT imaging of SCID mice with MCF7 xenografts, confirmed these observations. These results demonstrate that MUC1-FA-[18F] SFB may be a useful PET imaging probe for breast cancer detection and monitoring tumor response to the treatment.

Introduction: The purpose of the present work was to evaluate the imaging characteristics of 89Zr-PET in comparison with those obtained using fluorine-18 Fluorodeoxyglucose (18F-FDG) PET (a gold standard tracer in PET imaging) using a small-animal NanoScan PET/CT scanner. Methods: The system’s spatial resolution, sensitivity, uniformity, and image quality were measured on a Nano Scan small-animal PET/CT scanner according to the NEMA NU4-2008 protocols. For reconstruction images, we used 2D and 3D reconstruction algorithms. The reconstruction methods included filter back projection (FBP), the ordered subsets expectation maximization (OSEM) algorithm, and the 3D Tera-Tomo algorithm, which are developed for the NanoScan small-animal PET/CT scanner. Results: The results obtained showed a significant difference in the spatial resolution for 89Zr as compared to 22Na and 18F when using a 2D reconstruction algorithm. Where the spatial resolution values were much enhanced by using the 3D Tera-Tomo reconstruction for each isotope, the Full width at half maximum (FWHM) values were less than 1 for all isotopes at the center of the field of view (FOV). This difference in spatial resolution is dependent on the positron range, energy and the reconstruction method. Conclusion: The long half-life of 89Zr makes it an ideal positron emitter for performing immuno-PET, which is matched with the biological half-life of intact mAbs. 89Zr can also give several advantages over other long half-life positron emitters in relation to the overall imaging performance because of its relatively short positron range and simpler decay scheme. The values of 89Zr sensitivity that were obtained in the present study were less than those of previous studies.

Table of contentsOP03 Selective extraction of medically-related radionuclides from proton-irradiated thorium targetsV. Radchenko, J.W. Engle, C. Roy, J. Griswold, M.F. Nortier, E.R. Birnbaum, M. Brugh, S. Mirzadeh, K. D. John, M.E. FassbenderOP04 Comparison of [68Ga]FSC(succ-RGD)3 and [68Ga]NODAGA-RGD for PET imaging of αvβ3 integrin expressionChuangyan Zhai, Gerben M. Franssen, Milos Petrik, Peter Laverman, Clemens DecristoforoOP05 A new NPY-Y1R targeting peptide for breast cancer PET imagingAit-Mohand Samia, Dumulon-Perreault Véronique, Guérin BrigitteOP06 The influence of multivalency on CCK 2 receptor targetingD. Summer, A. Kroess, C. Rangger, H. Haas, P. Laverman, F. Gerben, E. von Guggenberg, C.DecristoforoOP07 SPECT Imaging of αvβ3 Expression by [99mTc(N)PNP43]- Bifunctional Chimeric RGD Peptide not Cross-Reacting with αvβ5Cristina Bolzati, Nicola Salvarese, Fiorenzo Refosco, Laura Meléndez-Alafort, Debora Carpanese, Antonio Rosato, Michele Saviano, Annarita Del Gatto, Daniela Comegna, Laura ZaccaroOP09 New dienophiles for the inverse-electron-demand Diels-Alder reaction and for pretargeted PET imagingEmilie Billaud, Muneer Ahamed, Frederik Cleeren, Elnaz Shahbazali, Tim Noël, Volker Hessel, Alfons Verbruggen and Guy BormansOP10 New complexing agent for Al18F-labelling of heat-sensitive biomolecules: Synthesis and preclinical evaluation of Al18F-RESCA1-HASCleeren F, Lecina J, Koole M, Verbruggen A and Bormans GOP11 A novel versatile precursor efficient for F-18 radiolabelling via click-chemistryB. Lugatoa, S. Stucchia, E.A. Turollaa, L. Giulianoa, S.Toddea, P. FerraboschibOP12 A general applicable method to quantify unidentified UV impurities in radiopharmaceuticalsR.P. Klok, M.P.J. Mooijer, N.H. Hendrikse, A.D. WindhorstOP13 Development of [18F]Fluoro-C-glycosides to radiolabel peptidesCollet C., Petry N., Chrétien F., Karcher G., Pellegrini-Moïse N., Lamandé-Langle S.OP14 A Microfluidic Approach for the 68Ga-labeling of PSMAHBED-CC and NODAGA-RGDSarah Pfaff, Cecile Philippe, Markus Mitterhauser, Marcus Hacker, Wolfgang WadsakOP16 Surprising reactivity of astatine in the nucleophilic substitution of aryliodonium salts: application to the radiolabeling of antibodiesFrançois Guérard, Yong-Sok Lee, Sébastien Gouard, Kwamena Baidoo, Cyrille Alliot, Michel Chérel, Martin W. Brechbiel, Jean-François GestinOP17 64Cu-NOTA-pertuzumab F(ab')2 fragments, a second-generation probe for PET imaging of the response of HER2-positive breast cancer to trastuzumab (Herceptin)Lam K, Chan C, Reilly RMOP18 Development of radiohalogenated analogues of a avb6-specific peptide for high LET particle emitter targeted radionuclide therapy of cancerSalomé Paillas, John Marshall, Jean-Pierre Pouget, Jane SosabowskiOP19 Ligand Specific Efficiency (LSE) as a guide in tracer optimizationEmmanuelle Briard, Yves P. Auberson, John Reilly, Mark Healy, David SykesOP23 The radiosynthesis of an 18F-labeled triglyceride, developed to visualize and quantify brown adipose tissue activityAndreas Paulus, Wouter van Marken Lichtenbelt,Felix Mottaghy,...

Background Myocardial perfusion imaging (MPI) is one of the most commonly performed investigations in nuclear medicine procedures. Due to the longer half-life of the emerging positron emitter copper-64 and its availability from low energy cyclotron, together with its well-known coordination chemistry, we have synthesized 64Cu-labeled NOTA- and 64Cu-NOTAM-rhodamine conjugates as potential cardiac imaging agents using PET. Results 64Cu-NOTA- and 64Cu-NOTAM-rhodamine conjugates were synthesized using a traightforward and one-step simple reaction. Radiochemical yields were greater than 97% (decay corrected), with a total synthesis time of less than 25 min. Radiochemical purities were always greater than 98% as assessed by TLC and HPLC. These synthetic approaches hold considerable promise as a simple method for 64Cu-rhodamine conjugates synthesis, with high radiochemical yield and purity. Biodistribution studies in normal Fischer rats at 60 min post-injection, demonstrated significant heart uptake and a good biodistribution profile for both the radioconjugates. However, the 64Cu-NOTAM-rhodamine conjugate has shown more heart uptake (~ 10% ID/g) over the 64Cu-NOTA-rhodamine conjugate (5.6% ID/g). Conclusions These results demonstrate that these radioconjugates may be useful probes for the PET evaluation of MPI.

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Background: There is a need to develop new and more potent radiofluorinated peptide and their hybrid conjugates for multiple-receptors targeting properties that overexpress on many cancers.Methods: We have synthesized MUC1-[18F]SFB and MUC1-FA-[18F]SFB hybrid conjugates using a convenient and one-step nucleophilic displacement reactions. In vitro cell binding and in vivo evaluation in animals were performed to determine the potential of these radiolabeled compounds.Results: Radiochemical yields for MUC1-[18F]SFB and MUC1-FA-[18F]SFB conjugates were greater than 70% in less than 30 min synthesis time. Radiochemical purities were greater than 97% without HPLC purification, which makes these approaches amenable for automation. In vitro studies on MCF7 breast cancer cells showed that the significant amounts of the radiofluorinated conjugates were associated with cell fractions and held good affinity and specificity for MCF7 cells. In vivo characterization in Balb/c mice revealed rapid blood clearance with excretion predominantly by urinary as well as hepatobiliary systems for MUC1-[18F]SFB and MUC1-FA-[18F]SFB, respectively.Biodistribution in SCID mice bearing MCF7 xenografts, demonstrated excellent tumor uptake (12% ID/g) and favorable kinetics for MUC1-FA-[18F]SFB over MUC1-[18F]SFB. The tumor uptake was blocked by the excess co-injection of cold peptides suggesting the receptor-mediated process.Conclusion: Initial PET/CT imaging of SCID mice with MCF7 xenografts, confirmed these observations. These results demonstrate that MUC1-FA-[18F]SFB may be a useful PET imaging probe for breast cancer detection and monitoring tumor response to the treatment.

Background: There is a need to develop new and more potent radiofluorinated peptide and their hybrid conjugates for multiple-receptors targeting properties that overexpress on many cancers. Methods: We have synthesized MUC1-[18F]SFB and MUC1-FA-[18F]SFB hybrid conjugates using a convenient and one-step nucleophilic displacement reactions. In vitro cell binding and in vivo evaluation in animals were performed to determine the potential of these radiolabeled compounds. Results: Radiochemical yields for MUC1-[18F]SFB and MUC1-FA-[18F]SFB conjugates were greater than 70% in less than 30 min synthesis time. Radiochemical purities were greater than 97% without HPLC purification, which make these approaches amenable for automation. In vitro studies on MCF7 breast cancer cells showed that the significant amounts of the radiofluorinated conjugates were associated with cell fractions and held good affinity and specificity for MCF7 cells. In vivo characterization in Balb/c mice revealed rapid blood clearance with excretion predominantly by urinary as well as hepatobiliary systems for MUC1-[18F]SFB and MUC1-FA-[18F]SFB, respectively. Biodistribution in SCID mice bearing MCF7 xenografts, demonstrated excellent tumor uptake (12% ID/g) and favorable kinetics for MUC1-FA-[18F]SFB over MUC1-[18F]SFB. The tumor uptake was blocked by the excess co-injection of cold peptides suggesting the receptor-mediated process. Conclusion: Initial PET/CT imaging of SCID mice with MCF7 xenografts, confirmed these observations. These results demonstrate that MUC1-FA-[18F]SFB may be useful PET imaging probe for breast cancer detection and monitoring tumor response to the treatment.