“Click Labeling” with 2-[¹⁸F]Fluoroethylazide for Positron Emission Tomography

As an effort in the development of more flexible 18F-labeling chemistry, we report herein on the use of the Cu(I)-catalyzed Huisgen cycloaddition, also known as the “click reaction”, to form 18F-labeled 1,2,3-triazoles. Nucleophilic fluorination of 2-azidoethyl-4-toluenesulfonate followed by distillation provided 2-[18F]fluoroethylazide in 55% radiochemical yield (decay-corrected). 2-[18F]fluoroethylazide was reacted with a small library of terminal alkynes in the presence of excess Cu2+/ascorbate or copper powder. The most reactive alkyne, N-benzylpropynamide provided nearly quantitative incorporation of 2-[18F]fluoroethylazide after 15 min at ambient temperature, whereas the majority of the alkyne substrates provided excellent yields of the corresponding 18F-labeled 1,2,3-triazoles following heating to 80 °C. Using the method described, a model peptide was obtained in 92.3 ± 0.3% (n = 3) radiochemical yield (decay-corrected) after purification by semipreparative HPLC

Design, Synthesis, and Biological Characterization of a Caspase 3/7 Selective Isatin Labeled with 2-[¹⁸F]fluoroethylazide

Imaging of programmed cell death (apoptosis) is important in the assessment of therapeutic response in oncology and for diagnosis in cardiac and neurodegenerative disorders. The executioner caspases 3 and 7 ultimately effect cellular death, thus providing selective molecular targets for in vivo quantification of apoptosis. To realize this potential, we aimed to develop 18F-labeled isatin sulfonamides with high metabolic stability and moderate lipophilicity while retaining selectivity and affinity for caspase 3/7. A small library of isatins modified with fluorinated aromatic groups and heterocycles was synthesized. A lead compound incorporating 2′-fluoroethyl-1,2,3-triazole was identified with subnanomolar affinity for caspase 3. “Click labeling” provided the 18F-labeled tracer in 65 ± 6% decay-corrected radiochemical yield from 2-[18F]fluoroethylazide. The compound showed high stability in vivo with rapid uptake and elimination in healthy tissues and tumor. The novel 18F-labeled isatin is a candidate radiotracer for further preclinical evaluation for imaging of apoptosis

Radiosynthesis and Biodistribution of Cyclic RGD Peptides Conjugated with Novel [¹⁸F]Fluorinated Aldehyde-Containing Prosthetic Groups

Achieving high-yielding, robust, and reproducible chemistry is a prerequisite for the 18F-labeling of peptides for quantitative receptor imaging using positron emission tomography (PET). In this study, we extend the toolbox of oxime chemistry to include the novel prosthetic groups [18F]-(2-{2-[2-(2-fluoroethoxy)ethoxy]ethoxy}ethoxy)acetaldehyde, [18F]5, and [18F]-4-(3-fluoropropoxy)benzaldehyde, [18F]9, in addition to the widely used 4-[18F]fluorobenzaldehyde, [18F]12. The three 18F-aldehydes were conjugated to the same aminooxy-bearing RGD peptide and the effect of the prosthetic group on biodistribution and tumor uptake studied in mice. The peptide conjugate [18F]7 was found to possess superior in vivo pharmacokinetics with higher tumor to blood, tumor to liver, tumor to muscle, and tumor to lung ratios than either [18F]10 or [18F]13. The radioactivity from the [18F]7 conjugate excreted more extensively through the kidney route with 79%id passing through the urine and bladder at the 2 h time point compared to around 55%id for the more hydrophobic conjugates [18F]10 and [18F]13. The chemical nature of a prosthetic group can be employed to tailor the overall biodistribution profile of the radiotracer. In this example, the hydrophilic nature of the ethylene glycol containing prosthetic group [18F]5 clearly influences the overall excretion pattern for the RGD peptide conjugate

Move S3 from Measurement of Tumor Antioxidant Capacity and Prediction of Chemotherapy Resistance in Preclinical Models of Ovarian Cancer by Positron Emission Tomography

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Move S1 from Measurement of Tumor Antioxidant Capacity and Prediction of Chemotherapy Resistance in Preclinical Models of Ovarian Cancer by Positron Emission Tomography

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Move S2 from Measurement of Tumor Antioxidant Capacity and Prediction of Chemotherapy Resistance in Preclinical Models of Ovarian Cancer by Positron Emission Tomography

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Move S4 from Measurement of Tumor Antioxidant Capacity and Prediction of Chemotherapy Resistance in Preclinical Models of Ovarian Cancer by Positron Emission Tomography

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Supplementary Data from Measurement of Tumor Antioxidant Capacity and Prediction of Chemotherapy Resistance in Preclinical Models of Ovarian Cancer by Positron Emission Tomography

Supplementary Figures 1 - 6. Fig. S1 shows the ability of PEO1, PEO4 and PEO6 cells to form colonies following cisplatin treatment; Fig. S2 demonstrates that [18F]FDG uptake in A2780 cells is unrelated to drug resistance; Fig. S3 examines the expression of key ABC transporters; Fig. S4 provides representative PET images of mice bearing A2780 WT and A2780 DoxR tumors; Fig. S5 quantifies the [18F]FSPG tumor-to-background ratio in WT and DoxR tumor-bearing mice; and Fig. S6 illustrates [18F]FSPG DoxR tumor retention after doxil treatment of mice.</p

Move S5 from Measurement of Tumor Antioxidant Capacity and Prediction of Chemotherapy Resistance in Preclinical Models of Ovarian Cancer by Positron Emission Tomography

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Movie S1 from Assessment of Tumor Redox Status through (<i>S</i>)-4-(3-[¹⁸F]fluoropropyl)-L-Glutamic Acid PET Imaging of System x_c⁻ Activity

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