ABSTRACT
To develop PET tracers for imaging of Alzheimer's disease, new carbon-11 labeled potent and selective PDE5 inhibitors have been synthesized. The reference standards (5) and (12), and their corresponding desmethylated precursors (6) and (13) were synthesized from methyl 2-amino-5-bromobenzoate and (4-methoxyphenyl)methanamine in multiple steps with 2%, 1%, 1% and 0.2% overall chemical yield, respectively. The radiotracers ([11C]5) and ([11C]12) were prepared from their corresponding precursors 6 and 13 with [11C]CH3OTf through O-11C-methylation and isolated by HPLC combined with SPE in 40-50% radiochemical yield, based on [11C]CO2 and decay corrected to EOB. The radiochemical purity was >99%, and the molar activity (Am) at EOB was in a range of 370-740 GBq/µmol.
Subject(s)
Alzheimer Disease/diagnostic imaging , Carbon Radioisotopes/chemistry , Phosphodiesterase 5 Inhibitors/chemical synthesis , Radiopharmaceuticals/chemical synthesis , Alzheimer Disease/enzymology , Chromatography, High Pressure Liquid , Chromatography, Reverse-Phase , Humans , Phosphodiesterase 5 Inhibitors/chemistry , Positron-Emission Tomography/methods , Radioligand Assay , Radiopharmaceuticals/chemistry , Vardenafil Dihydrochloride/analogs & derivatives , Vardenafil Dihydrochloride/chemical synthesis , Vardenafil Dihydrochloride/chemistryABSTRACT
Sulfoximines have gained considerable recognition as an important structural motif in drug discovery of late. In particular, the clinical kinase inhibitors for the treatment of cancer, roniciclib (pan-CDK inhibitor), BAYâ 1143572 (P-TEFb inhibitor), and AZDâ 6738 (ATR inhibitor), have recently drawn considerable attention. Whilst the interest in this underrepresented functional group in drug discovery is clearly on the rise, there remains an incomplete understanding of the medicinal-chemistry-relevant properties of sulfoximines. Herein we report the synthesis and inâ vitro characterization of a variety of sulfoximine analogues of marketed drugs and advanced clinical candidates to gain a better understanding of this neglected functional group and its potential in drug discovery.