Synthesis of 6-acrylamido-4-(2-[18F]fluoroanilino)quinazoline: A prospective irreversible EGFR binding probe

Acrylamido-quinazolines substituted at the 6-position bind irreversibly to the intracellular ATP binding domain of the epidermal growth factor receptor (EGFR). A general route was developed for preparing 6-substituted-4-anilinoquinazolines from [18F]fluoroanilines for evaluation as EGFR targeting agents with PET. By a cyclization reaction, 2-[18F]fluoroaniline was reacted with N'-(2-cyano-4-nitrophenyl)-N,N-dimethylimidoformamide to produce 6-nitro-4-(2-[18F]fluoroanilino)quinazoline in 27.5 percent decay-corrected radiochemical yield. Acid mediated tin chloride reduction of the nitro group was achieved in 5 min (80 percent conversion) and subsequent acylation with acrylic acid gave 6-acrylamido-4-(2-[18F]fluoroanilino)quinazoline in 8.5 percent decay-corrected radiochemical yield, from starting fluoride, in less than 2 hours

Low Incidence of Corticosteroid-associated Adverse Events on Long-term Exposure to Low-dose Prednisone Given with Abiraterone Acetate to Patients with Metastatic Castration-resistant Prostate Cancer

Background: Abiraterone acetate (AA) is the prodrug of abiraterone, which inhibits CYP17A1 and testosterone synthesis and prolongs the survival of patients with metastatic castration-resistant prostate cancer (mCRPC). AA plus prednisone (P) (AA + P) is approved for the treatment of patients with mCRPC. Objective: To investigate whether long-term use of low-dose P with or without AA leads to corticosteroid-associated adverse events (CA-AEs) in mCRPC patients. Design, setting, and participants: The study included 2267 patients in COU-AA-301 and COU-AA-302. We used an inclusive Standardized MedDRA Queries-oriented approach to identify 112 preferred terms for known CA-AEs, and assessed the incidence of CA-AEs during 3-mo exposure intervals and across all P exposure levels. Intervention: All 2267 patients received 5 mg of P twice daily, and 1333/2267 received AA (1 g) plus P. Results and limitations: The CA-AE incidence after any P exposure was 25%, 26%, and 23% for any grade, and 5%, 5%, and 4% for grade >= 3 CA-AEs for all patients and the AA + P and P alone groups, respectively. The most common any-grade CA-AEs were hyperglycemia (7.4%, 7.8%, and 6.9% for all patients, AA + P, and P alone, respectively) and weight increase (4.3%, 3.9%, and 4.8%, respectively). When assessed by duration of exposure (3-mo intervals up to >= 30 mo), no discernable trend was observed for CA-AEs, including hyperglycemia and weight increase. The investigator-reported study discontinuation rate due to CA-AEs was 11/2267 (0.5%), and one patient had a CA-AE resulting in death. Conclusions: Low-dose P given with or without AA is associated with low overall incidence of CA-AEs. The frequency of CA-AEs remained low with increased duration of exposure to P. Patient summary: We assessed adverse events in patients with metastatic castration resistant prostate cancer during long-term treatment with a low dose of a corticosteroid. We found that long-term treatment with this low-dose corticosteroid is safe and tolerable. (C) 2016 European Association of Urology. Published by Elsevier B.V. All rights reserved