scholarly journals Synthesis and Preclinical Evaluation of [18F]PF04217903, a Selective MET PET Tracer

2020 ◽  
Author(s):  
Vegard Torp Lien ◽  
Emily Hauge ◽  
Syed Nuruddin ◽  
Jo Klaveness ◽  
Dag Erlend Olberg
Keyword(s):  
Growth Factor Receptor ◽  
Radiochemical Yield ◽  
Molar Activity ◽  
Bioisosteric Replacement ◽  
Pet Tracer ◽  
Positron Emission ◽  
Wide Range ◽  
Hepatocyte Growth

<p>The tyrosine kinase MET (hepatocyte growth factor receptor) is abnormally activated in a wide range of cancers and is often correlated with a poor prognosis. Precision medicine with positron emission tomography (PET) can potentially aid in the assessment of tumor biochemistry and heterogeneity, which can prompt the selection of the most effective therapeutic regimes. The selective MET inhibitor PF04217903 (<b>1</b>) formed the basis for a bioisosteric replacement to the deoxyfluorinated analogue [<sup>18</sup>F]<b>2</b>, intended as a PET tracer for MET. [<sup>18</sup>F]<b>2 </b>could be synthesized with a “hydrous fluoroethylation” protocol in 6.3 ± 2.6% radiochemical yield and a molar activity of >50 GBq/µmol. <i>In vitro</i> autoradiography indicated that [<sup>18</sup>F]<b>2 </b>specifically binds to MET in PC3 tumor tissue, and <i>in vivo</i> biodistribution in mice showed predominantly a hepatobiliary excretion along with a low retention of radiotracer in other organs. </p>

scholarly journals Synthesis and Preclinical Evaluation of [18F]PF04217903, a Selective MET PET Tracer

2020 ◽  
Author(s):  
Vegard Torp Lien ◽  
Emily Hauge ◽  
Syed Nuruddin ◽  
Jo Klaveness ◽  
Dag Erlend Olberg
Keyword(s):  
Growth Factor Receptor ◽  
Radiochemical Yield ◽  
Molar Activity ◽  
Bioisosteric Replacement ◽  
Pet Tracer ◽  
Positron Emission ◽  
Wide Range ◽  
Hepatocyte Growth

<p>The tyrosine kinase MET (hepatocyte growth factor receptor) is abnormally activated in a wide range of cancers and is often correlated with a poor prognosis. Precision medicine with positron emission tomography (PET) can potentially aid in the assessment of tumor biochemistry and heterogeneity, which can prompt the selection of the most effective therapeutic regimes. The selective MET inhibitor PF04217903 (<b>1</b>) formed the basis for a bioisosteric replacement to the deoxyfluorinated analogue [<sup>18</sup>F]<b>2</b>, intended as a PET tracer for MET. [<sup>18</sup>F]<b>2 </b>could be synthesized with a “hydrous fluoroethylation” protocol in 6.3 ± 2.6% radiochemical yield and a molar activity of >50 GBq/µmol. <i>In vitro</i> autoradiography indicated that [<sup>18</sup>F]<b>2 </b>specifically binds to MET in PC3 tumor tissue, and <i>in vivo</i> biodistribution in mice showed predominantly a hepatobiliary excretion along with a low retention of radiotracer in other organs. </p>

scholarly journals Synthesis and Biological Evaluation of a Radiolabeled PET Probe for Visualization of In Vivo α-Fucosidase Expression

2021 ◽  
Vol 14 (8) ◽  
pp. 745
Author(s):  
Jonathan Cotton ◽  
Chris Marc Goehring ◽  
Anna Kuehn ◽  
Andreas Maurer ◽  
Kerstin Fuchs ◽  
...  
Keyword(s):  
Ex Vivo ◽  
Sodium Hydride ◽  
Biological Evaluation ◽  
Tracer Uptake ◽  
Mouse Serum ◽  
Molar Activity ◽  
Pet Tracer ◽  
Positron Emission

The acidic hydrolase α-fucosidase (AF) is a biomarker for maladies such as cancer and inflammation. The most advanced probes for α-fucosidase are unfortunately constrained to ex vivo or in vitro applications. The in vivo detection and quantification of AF using positron emission tomography would allow for better discovery and diagnosis of disease as well as provide better understanding of disease progression. We synthesized, characterized, and evaluated a radiolabeled small molecule inhibitor of AF based on a known molecule. The radiosynthesis involved the 11C methylation of a phenoxide, which was generated in situ by ultrasonification of the precursor with sodium hydride. The tracer was produced with a decay corrected yield of 41.7 ± 16.5% and had a molar activity of 65.4 ± 30.3 GBq/μmol. The tracer was shown to be stable in mouse serum at 60 min. To test the new tracer, HCT116 colorectal carcinoma cells were engineered to overexpress human AF. In vitro evaluation revealed 3.5-fold higher uptake in HCT116AF cells compared to HCT116 controls (26.4 ± 7.8 vs. 7.5 ± 1.0 kBq/106 cells). Static PET scans 50 min post injection revealed 2.5-fold higher tracer uptake in the HCT116AF tumors (3.0 ± 0.8%ID/cc (n = 6)) compared with the controls (1.2 ± 0.8 (n = 5)). Dynamic scans showed higher uptake in the HCT116AF tumors at all time-points (n = 2). Ex vivo analysis of the tumors, utilizing fluorescent DDK2 antibodies, confirmed the expression of human AF in the HCT116AF xenografts. We have developed a novel PET tracer to image AF in vivo and will now apply this to relevant disease models.

scholarly journals Evaluation of Organo [18F]Fluorosilicon Tetrazine as a Prosthetic Group for the Synthesis of PET Radiotracers

Molecules ◽  
2020 ◽  
Vol 25 (5) ◽  
pp. 1208 ◽  
Author(s):  
Sofia Otaru ◽  
Surachet Imlimthan ◽  
Mirkka Sarparanta ◽  
Kerttuli Helariutta ◽  
Kristiina Wähälä ◽  
...  
Keyword(s):  
Radiochemical Yield ◽  
Biological Evaluation ◽  
Prosthetic Group ◽  
Molar Activity ◽  
Positron Emission ◽  
Biological Studies ◽  
Model Protein ◽  
Improved Stability

Fluorine-18 is the most widely used positron emission tomography (PET) radionuclide currently in clinical application, due to its optimal nuclear properties. The synthesis of 18F-labeled radiotracers often requires harsh reaction conditions, limiting the use of sensitive bio- and macromolecules as precursors for direct radiolabeling with fluorine-18. We aimed to develop a milder and efficient in vitro and in vivo labeling method for trans-cyclooctene (TCO) functionalized proteins, through the bioorthogonal inverse-electron demand Diels-Alder (IEDDA) reaction with fluorine-18 radiolabeled tetrazine ([18F]SiFA-Tz). Here, we used TCO-modified bovine serum albumin (BSA) as the model protein, and isotopic exchange (IE) (19F/18F) chemistry as the labeling strategy. The radiolabeling of albumin-TCO with [18F]SiFA-Tz ([18F]6), providing [18F]fluoroalbumin ([18F]10) in high radiochemical yield (99.1 ± 0.2%, n = 3) and a molar activity (MA) of 1.1 GBq/µmol, confirmed the applicability of [18F]6 as a quick in vitro fluorination reagent for the TCO functionalized proteins. While the biological evaluation of [18F]6 demonstrated defluorination in vivo, limiting the utility for pretargeted applications, the in vivo stability of the radiotracer was dramatically improved when [18F]6 was used for the radiolabeling of albumin-TCO ([18F]10) in vitro, prior to administration. Due to the detected defluorination in vivo, structural optimization of the prosthetic group for improved stability is needed before further biological studies and application of pretargeted PET imaging.

Click Chemistry Expedited Radiosynthesis: Sulfur [18F]fluoride Exchange of Aryl Fluorosulfates

2019 ◽  
Author(s):  
Qinheng Zheng ◽  
Hongtao Xu ◽  
Hua Wang ◽  
Wen-Ge Han Du ◽  
Nan Wang ◽  
...  
Keyword(s):  
Click Chemistry ◽  
High Performance ◽  
Isotopic Exchange ◽  
Tumor Imaging ◽  
Radiochemical Yield ◽  
Exchange Method ◽  
Molar Activity ◽  
Positron Emission ◽  
Sulfur Fluoride

The lack of simple, efficient [<sup>18</sup>F]fluorination processes and new target-specific organofluorine probes remains the major challenge of fluorine-18-based positron emission tomography (PET). We report here a fast isotopic exchange method for the radiosynthesis of aryl [<sup>18</sup>F]fluorosulfate based PET agents enabled by the emerging sulfur fluoride exchange (SuFEx) click chemistry. The method has been applied to the fully-automated <sup>18</sup>F-radiolabeling of twenty-five structurally diverse aryl fluorosulfates with excellent radiochemical yield (83–100%) and high molar activity (up to 281 GBq µmol<sup>–1</sup>) at room temperature in 30 seconds. The purification of radiotracers requires no time-consuming high-performance liquid chromatography (HPLC), but rather a simple cartridge filtration. The utility of aryl [<sup>18</sup>F]fluorosulfate is demonstrated by the <i>in vivo</i> tumor imaging by targeting poly(ADP-ribose) polymerase 1 (PARP1).

scholarly journals 11C-Labeled Pictilisib (GDC-0941) as a Molecular Tracer Targeting Phosphatidylinositol 3-Kinase (PI3K) for Breast Cancer Imaging

2019 ◽  
Vol 2019 ◽  
pp. 1-11 ◽  
Author(s):  
Na Han ◽  
Yaqun Jiang ◽  
Yongkang Gai ◽  
Qingyao Liu ◽  
Lujie Yuan ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Pik3ca Mutation ◽  
Phosphatidylinositol 3 Kinase ◽  
Pet Tracer ◽  
Positron Emission ◽  
Pet Scans ◽  
Mcf 7 ◽  
Phosphatidylinositol 3

Pictilisib (GDC-0941) is an inhibitor of phosphatidylinositol 3-kinase (PI3K), part of a signaling cascade involved in breast cancer development. The purpose of this study was to evaluate the pharmacokinetics of pictilisib noninvasively by radiolabeling it with 11C and to assess the usability of the resulting [11C]-pictilisib as a positron-emission tomography (PET) tracer to screen for pictilisib-sensitive tumors. In this study, pictilisib was radiolabeled with [11C]-methyl iodide to obtain 11C-methylated pictilisib ([11C]-pictilisib) using an automated synthesis module with a high radiolabeling yield. Considerably higher uptake ratios were observed in MCF-7 (PIK3CA mutation, pictilisib-sensitive) cells than those in MDA-MB-231 (PIK3CA wild-type, pictilisib-insensitive) cells at all evaluated time points, indicating good in vitro binding of [11C]-pictilisib. Dynamic micro-PET scans in mice and biodistribution results showed that [11C]-pictilisib was mainly excreted via the hepatobiliary tract into the intestines. MCF-7 xenografts could be clearly visualized on the static micro-PET scans, while MDA-MB-231 tumors could not. Biodistribution results of two xenograft models showed significantly higher uptake and tumor-to-muscle ratios in the MCF-7 xenografts than those in MDA-MB-231 xenografts, exhibiting high in vivo targeting specificity. In conclusion, [11C]-pictilisib was first successfully prepared, and it exhibited good potential to identify pictilisib-sensitive tumors noninvasively, which may have a great impact in the treatment of cancers with an overactive PI3K/Akt/mTOR signal pathway. However, the high activity in hepatobiliary system and intestines needs to be addressed.

scholarly journals A Novel PET Imaging Using64Cu-Labeled Monoclonal Antibody against Mesothelin Commonly Expressed on Cancer Cells

2015 ◽  
Vol 2015 ◽  
pp. 1-15 ◽  
Author(s):  
Kazuko Kobayashi ◽  
Takanori Sasaki ◽  
Fumiaki Takenaka ◽  
Hiromasa Yakushiji ◽  
Yoshihiro Fujii ◽  
...  
Keyword(s):  
Monoclonal Antibody ◽  
Cancer Cells ◽  
Pet Imaging ◽  
Ex Vivo ◽  
Chelating Agent ◽  
Pancreatic Cancer Cells ◽  
Positron Emission ◽  
Wide Range

Mesothelin (MSLN) is a 40-kDa cell differentiation-associated glycoprotein appearing with carcinogenesis and is highly expressed in many human cancers, including the majority of pancreatic adenocarcinomas, ovarian cancers, and mesotheliomas, while its expression in normal tissue is limited to mesothelial cells lining the pleura, pericardium, and peritoneum. Clone 11-25 is a murine hybridoma secreting monoclonal antibody (mAb) against human MSLN. In this study, we applied the 11-25 mAb toin vivoimaging to detect MSLN-expressing tumors. Inin vitroandex vivoimmunochemical studies, we demonstrated specificity of 11-25 mAb to membranous MSLN expressed on several pancreatic cancer cells. We showed the accumulation of Alexa Fluor 750-labeled 11-25 mAb in MSLN-expressing tumor xenografts in athymic nude mice. Then, 11-25 mAb was labeled with64Cu via a chelating agent DOTA and was used in bothin vitrocell binding assay andin vivopositron emission tomography (PET) imaging in the tumor-bearing mice. We confirmed that64Cu-labeled 11-25 mAb highly accumulated in MSLN-expressing tumors as compared to MSLN-negative ones. The64Cu-labeled 11-25 mAb is potentially useful as a PET probe capable of being used for wide range of tumors, rather than18F-FDG that occasionally provides nonspecific accumulation into the inflammatory lesions.

scholarly journals [18F]SuFEx Click Chemistry Enabled Ultrafast Late-stage Radiosynthesis

2020 ◽  
Author(s):  
Qinheng Zheng ◽  
Hongtao Xu ◽  
Hua Wang ◽  
Wen-Ge Han Du ◽  
Nan Wang ◽  
...  
Keyword(s):  
Click Chemistry ◽  
High Performance ◽  
Isotopic Exchange ◽  
Tumor Imaging ◽  
Radiochemical Yield ◽  
Exchange Method ◽  
Molar Activity ◽  
Positron Emission ◽  
Sulfur Fluoride

The lack of simple, efficient [<sup>18</sup>F]fluorination processes and new target-specific organofluorine probes remains the major challenge of fluorine-18-based positron emission tomography (PET). We report here a fast isotopic exchange method for the radiosynthesis of aryl [<sup>18</sup>F]fluorosulfate based PET agents enabled by the emerging sulfur fluoride exchange (SuFEx) click chemistry. The method has been applied to the fully-automated <sup>18</sup>F-radiolabeling of twenty-five structurally diverse aryl fluorosulfates with excellent radiochemical yield (83–100%) and high molar activity (up to 281 GBq µmol<sup>–1</sup>) at room temperature in 30 seconds. The purification of radiotracers requires no time-consuming high-performance liquid chromatography (HPLC), but rather a simple cartridge filtration. The utility of aryl [<sup>18</sup>F]fluorosulfate is demonstrated by the <i>in vivo</i> tumor imaging by targeting poly(ADP-ribose) polymerase 1 (PARP1).

[18F]SuFEx Click Chemistry Enabled Ultrafast Late-stage Radiosynthesis

2020 ◽  
Author(s):  
Qinheng Zheng ◽  
Hongtao Xu ◽  
Hua Wang ◽  
Wen-Ge Han Du ◽  
Nan Wang ◽  
...  
Keyword(s):  
Click Chemistry ◽  
High Performance ◽  
Isotopic Exchange ◽  
Tumor Imaging ◽  
Radiochemical Yield ◽  
Exchange Method ◽  
Molar Activity ◽  
Positron Emission ◽  
Sulfur Fluoride

The lack of simple, efficient [<sup>18</sup>F]fluorination processes and new target-specific organofluorine probes remains the major challenge of fluorine-18-based positron emission tomography (PET). We report here a fast isotopic exchange method for the radiosynthesis of aryl [<sup>18</sup>F]fluorosulfate based PET agents enabled by the emerging sulfur fluoride exchange (SuFEx) click chemistry. The method has been applied to the fully-automated <sup>18</sup>F-radiolabeling of twenty-five structurally diverse aryl fluorosulfates with excellent radiochemical yield (83–100%) and high molar activity (up to 281 GBq µmol<sup>–1</sup>) at room temperature in 30 seconds. The purification of radiotracers requires no time-consuming high-performance liquid chromatography (HPLC), but rather a simple cartridge filtration. The utility of aryl [<sup>18</sup>F]fluorosulfate is demonstrated by the <i>in vivo</i> tumor imaging by targeting poly(ADP-ribose) polymerase 1 (PARP1).

scholarly journals Design, Synthesis, Computational, and Preclinical Evaluation of natTi/45Ti-Labeled Urea-Based Glutamate PSMA Ligand

Molecules ◽  
2020 ◽  
Vol 25 (5) ◽  
pp. 1104 ◽  
Author(s):  
Kristina Søborg Pedersen ◽  
Christina Baun ◽  
Karin Michaelsen Nielsen ◽  
Helge Thisgaard ◽  
Andreas Ingemann Jensen ◽  
...  
Keyword(s):  
Computer Aided Design ◽  
Ex Vivo ◽  
Design Synthesis ◽  
Psma Ligand ◽  
Pet Tracer ◽  
Positron Emission ◽  
Tumor Accumulation ◽  
Aided Design

Despite promising anti-cancer properties in vitro, all titanium-based pharmaceuticals have failed in vivo. Likewise, no target-specific positron emission tomography (PET) tracer based on the radionuclide 45Ti has been developed, notwithstanding its excellent PET imaging properties. In this contribution, we present liquid–liquid extraction (LLE) in flow-based recovery and the purification of 45Ti, computer-aided design, and the synthesis of a salan-natTi/45Ti-chelidamic acid (CA)-prostate-specific membrane antigen (PSMA) ligand containing the Glu-urea-Lys pharmacophore. The compound showed compromised serum stability, however, no visible PET signal from the PC3+ tumor was seen, while the ex vivo biodistribution measured the tumor accumulation at 1.1% ID/g. The in vivo instability was rationalized in terms of competitive citrate binding followed by Fe(III) transchelation. The strategy to improve the in vivo stability by implementing a unimolecular ligand design is presented.

scholarly journals Feasibility of Developing Radiotracers for MDM2: Synthesis and Preliminary Evaluation of an 18F-Labeled Analogue of the MDM2 Inhibitor SP-141

2021 ◽  
Vol 14 (4) ◽  
pp. 358
Author(s):  
Satish K. Chitneni ◽  
Zhengyuan Zhou ◽  
Brian E. Watts ◽  
Michael R. Zalutsky
Keyword(s):  
Negative Regulator ◽  
Cell Uptake ◽  
Preliminary Evaluation ◽  
In Vivo Evaluation ◽  
Normal Tissues ◽  
Pet Tracer ◽  
Positron Emission ◽  
Mdm2 Expression

Murine double minute 2 (MDM2), a negative regulator of the p53 tumor suppressor protein, is overexpressed in several human cancers. Herein we investigate the feasibility of developing 18F-labeled compounds based on the small molecule inhibitor SP-141 for imaging tumor MDM2 expression levels with positron emission tomography (PET). Three nonradioactive fluorinated SP-141 analogues, 1–3, were synthesized, and their binding to the MDM2 protein was analyzed by surface plasmon resonance (SPR). One of these, a fluoroethoxy analogue, was labeled with fluorine-18 (18F) using 18F-fluorethyl bromide to provide [18F]1 and evaluated in vitro and in vivo. SPR analysis confirmed the binding of the fluorinated analogues to MDM2 at 1.25–20 µM concentrations. Cell uptake studies revealed high uptake (67.5–71.4 %/mg protein) and specificity of [18F]1 in MCF7 and HepG2 cells. The uptake of [18F]1 in these cells could be modulated using 100 µM SP-141, potentially reflecting changes in MDM2 expression because of p53 activation by SP-141. [18F]1 exhibited stable uptake and retention in HepG2 tumor xenografts (~3 %ID/g) in vivo, but poor clearance from blood and other normal tissues, yielding low tumor-to-background ratios (< 2) at 2 h post injection. Our results suggest that [18F]1 has suboptimal characteristics for in vivo evaluation as a PET tracer for MDM2, but warrant radiolabeling and assessment of the other fluorinated analogues synthesized in this work, 2 and 3, and potentially other molecular scaffolds for developing MDM2 targeted radiotracers.

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