کد مقاله کد نشریه سال انتشار مقاله انگلیسی نسخه تمام متن
10585527 981368 2013 8 صفحه PDF دانلود رایگان
عنوان انگلیسی مقاله ISI
Synthesis, radiosynthesis and first in vitro evaluation of novel PET-tracers for the dopamine transporter: [11C]IPCIT and [18F]FE@IPCIT
موضوعات مرتبط
مهندسی و علوم پایه شیمی شیمی آلی
پیش نمایش صفحه اول مقاله
Synthesis, radiosynthesis and first in vitro evaluation of novel PET-tracers for the dopamine transporter: [11C]IPCIT and [18F]FE@IPCIT
چکیده انگلیسی
IntroductionPresent data indicate that merging beneficial structural elements from previously published DAT-ligands highest DAT affinity, selectivity and a suitable metabolic profile should be achieved. This combination led to the development of IPCIT and FE@IPCIT.MethodsPrecursor synthesis was done starting from cocaine in a six step reaction. O-[11C]-methylation was established using [11C]methyl iodide, optimized and subsequently automated. Small scale 18F-fluroroethylation as well as optimization of reaction parameters and automation were performed. Affinity and selectivity of the candidate substances were tested in standard binding experiments on human membranes. Metabolic stability and blood-brain-barrier (BBB) penetration were determined.ResultsPrecursor compound, IPCITacid, and reference compounds, IPCIT and FE@IPCIT, were obtained in 4.9%, 12.7% and 4.1% yield, respectively. Automated radiosynthesis of [11C]IPCIT yielded 1.9 ± 0.7 GBq (12.5 ± 4%, corrected for decay). Optimum parameters for 18F-fluoroethylation were 110 °C for 15 min under TBAH catalysis, yielding 67 ± 16% radiochemical incorporation. Affinity was determined as 1.7 ± 0.6 nM for IPCIT, 1.3 ± 0.2 nM for FE@IPCIT and 37 ± 13 nM for the precursor molecule, IPCIT-acid. Results from in vitro and in silico evaluations revealed high stability but also high lipophilicity.ConclusionPresent data indicate high affinity and stability of both IPCIT and FE@IPCIT. Radiolabelling, optimization of reaction parameters and automation succeeded. On the other hand, data concerning BBB-penetration are not promising.
ناشر
Database: Elsevier - ScienceDirect (ساینس دایرکت)
Journal: Bioorganic & Medicinal Chemistry - Volume 21, Issue 24, 15 December 2013, Pages 7562-7569
نویسندگان
, , , , , , , , , , , ,