ABSTRACT
Inhibition of the sodium-glucose cotransporter 2 (SGLT2) by canagliflozin in type 2 diabetes mellitus results in large between-patient variability in clinical response. To better understand this variability, the positron emission tomography (PET) tracer [18F]canagliflozin was developed via a Cu-mediated 18F-fluorination of its boronic ester precursor with a radiochemical yield of 2.0 ± 1.9% and a purity of >95%. The GMP automated synthesis originated [18F]canagliflozin with a yield of 0.5-3% (n = 4) and a purity of >95%. Autoradiography showed [18F]canagliflozin binding in human kidney sections containing SGLT2. Since [18F]canagliflozin is the isotopologue of the extensively characterized drug canagliflozin and thus shares its toxicological and pharmacological characteristics, it enables its immediate use in patients.
Subject(s)
Canagliflozin/chemical synthesis , Fluorine Radioisotopes , Molecular Imaging/methods , Positron-Emission Tomography/methods , Sodium-Glucose Transporter 2 Inhibitors/chemical synthesis , Sodium-Glucose Transporter 2/analysis , Humans , Radioactive TracersABSTRACT
INTRODUCTION: Fluorine-18 labeled positron emission tomography (PET) tracers were developed to obtain more insight into the function of P-glycoprotein (P-gp) in relation to various conditions. They allow research in facilities without a cyclotron as they can be transported with a half-life of 110â¯min. As the metabolic stability of previously reported tracers [18F]1 and [18F]2 was poor, the purpose of this study was to improve this stability using deuterium substitution, creating verapamil analogs [18F]1-d4, [18F]2-d4, [18F]3-d3 and [18F]3-d7. METHODS: The following deuterium containing tracers were synthesized and evaluated in mice and rats: [18F]1-d4, [18F]2-d4, [18F]3-d3 and [18F]3-d7. RESULTS: The deuterated analogs [18F]2-d4, [18F]3-d3 and [18F]3-d7 showed increased metabolic stability compared with their non-deuterated counterparts. The increased metabolic stability of the methyl containing analogs [18F]3-d3 and [18F]3-d7 might be caused by steric hindrance for enzymes. CONCLUSION: The striking similar in vivo behavior of [18F]3-d7 to that of (R)-[11C]verapamil, and its improved metabolic stability compared with the other fluorine-18 labeled tracers synthesized, supports the potential clinical translation of [18F]3-d7 as a PET radiopharmaceutical for P-gp evaluation.
Subject(s)
Fluorine Radioisotopes , Verapamil/chemistry , Verapamil/metabolism , Animals , Drug Stability , Isotope Labeling , Male , Positron-Emission Tomography , Radioactive Tracers , Radiochemistry , Rats , Rats, WistarABSTRACT
The design and synthesis of three novel polycyclic scaffolds containing sulfoximines are presented in this work, which exemplify that sulfoximines represent a real opportunity for the discovery of new drug candidates. Additionally, the structures present at least two points of diversification and contain a high level of sp3-character, hence being very interesting 3D scaffolds. The compounds synthesized were added to the compound collection of the European Lead Factory.
Subject(s)
Polycyclic Compounds/chemical synthesis , Small Molecule Libraries/chemical synthesis , Sulfoxides/chemical synthesis , Bridged Bicyclo Compounds, Heterocyclic/chemical synthesis , Cycloaddition Reaction , Drug Discovery , Molecular Structure , Pyrazoles/chemical synthesis , Pyrazoles/chemistry , Spiro Compounds/chemical synthesis , StereoisomerismABSTRACT
BACKGROUND: Ultrasonography is considered useful to distinguish between solid and cystic thyroid nodules and to stratify a nodule's risk of cancer as low, medium, or high. Ultrasound (US) elastography has been applied to study the hardness/elasticity of nodules to differentiate malignant from benign lesions. Elastography possibly can solve the dilemma in reaching an accurate diagnosis for the cytologically known as indeterminate nodules. AIM: To evaluate the sensitivity and specificity of US elastography in the diagnosis of thyroid cancer. PATIENTS AND METHODS: This prospective study included 40 patients. The total number of nodules was 46, they were all euthyroid. Laboratory investigations were done including FT3, FT4, and TSH to exclude hot nodules. Neck US, US elastography, and fine-needle aspiration were done to all patients, and US elastography scoring system from 1 to 4 was used. RESULTS: Four out of the 46 studied nodules were malignant. The ROC curve for elastography score (E-score) showed high sensitivity, specificity for the diagnosis of malignant thyroid nodules with a cut-off value of E-score 4 and high significance (p<0.001), the area under curve was 0.92. The sensitivity was 75.0% and specificity was 100%. For E-score more than 2, the sensitivity was 100% and specificity was 85.37%. CONCLUSION: US elastography can be used to increase both the sensitivity and the specificity of US for the detection of malignant thyroid nodules, and so it seems to have great potential as a new tool for the diagnosis of thyroid cancer.
