N‐2‐(4‐N‐(4‐[¹⁸F]Fluorobenzamido)phenyl)‐propyl‐2‐propanesulphonamide: synthesis and radiofluorination of a putative AMPA receptor ligand

Abstract

Arylpropylsulphonamides are in the focus of research as a-amino-3-hydroxy-5-methyl-4-isoxazolpropionic acid (AMPA) receptor ligands. A new fluorine-18-labelled potentiator of AMPA receptors was synthesized as a potential radiotracer for cerebral imaging with positron emission tomography. Using N-2-(4-N-(4-nitrobenzamido)-phenyl)-propyl-2-propanesulphonamide (7) Optimization of the reaction parameters time, temperature, solvent and concentration gave a radiochemical yield of 38 AE 8% at 1808C in dimethylsulphoxide within 30-min reaction time. After a solid-phase extraction followed by a high-performance liquid chromatography separation, the product could be obtained in radiochemical yields of 5 AE 1.5%. Radiochemical purity was higher than 95% and the specific activity amounted to 77 AE 40 GBq/mmol. First in vitro assays with rat brain slices revealed a high non-specific binding and a uniform distribution of [ 18 F]8 not lending it for in vivo imaging purposes.

Positron Emission Tomography (PET) Ligand Development for Ionotropic Glutamate Receptors: Challenges and Opportunities for Radiotracer Targeting N-Methyl-d-aspartate (NMDA), α-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid (AMPA), and Kainate Receptors

“…The brain uptake of [ 11 C] 48 reached a peak at 2–3 min p.i., followed by a decrease then a gradual increased uptake at later time point, which may be caused by polar brain penetrant radiometabolites. Another potentiator-type tracer was developed by 18 F-labeling of a LY395153 ( 49 , Figure ) derivative ([ 18 F] 50 ) . However, unlike LY395153, cold compound 50 failed to potentiate the [ 3 H]­AMPA binding on frozen brain slices.…”

Radiosynthesis of carbon‐11 and fluorine‐18 labelled radiotracers to image the ionotropic and metabotropic glutamate receptors

“…Another positive modulator, N ‐2‐(4‐ N ‐(4‐[ 18 F]fluorobenzamido)phenyl)‐propyl‐2‐propanesulphamide ( 9 , Figure ) was radiolabelled by nucleophilic substitution from the 4‐nitro precursor with a weak RCY of 5% and an SRA of 77 ± 40 GBq/µmol. The poor activation of the aromatic leaving group involved a 30‐min reaction time at 180 °C in DMSO for an incorporation yield of 38 ± 8% . This radiolabelled potentiator presented a high nonspecific binding not compatible with PET imaging.…”