Novel fluorine-18 PET radiotracers based on flumazenil for GABAA imaging in the brain

Abstract

Introduction Two 7-fluoroimidazobenzodiazepines (AH114726 and GEH120348), analogs of flumazenil, were labeled with fluorine-18 and evaluated as alternative radioligands for in vivo imaging of the GABAA/benzodiazepine receptor by comparing them to [11C]flumazenil in rhesus monkey. Methods Radiotracers were prepared from the corresponding nitro-precursors in an automated synthesis module, and primate imaging studies were conducted on a Concorde MicroPET P4 scanner. The brain was imaged for 60 (12 × 5 min frames) or 90 min (18 × 5 min frames), and data was reconstructed using the 3D MAP algorithm. Specificity of [18F]AH114726 and [18F]GEH120348 was confirmed by displacement studies using unlabeled flumazenil. Results [18F]GEH120348 and [18F]AH114726 were obtained in 13–24% yields (end of synthesis) with high chemical (>95%) and radiochemical (>99%) purities, and high specific activities (2061 ± 985 Ci/mmol). The in vivo pharmacokinetics of [18F]AH114726 and [18F]GEH120348 were determined in a non-human primate and directly compared with [11C]flumazenil. Both fluorine-18 radioligands showed time-dependent regional brain distributions that correlated with the distribution of [11C]flumazenil and the known concentrations of GABAA/benzodiazepine receptors in the monkey brain. [18F]AH114726 exhibited maximal brain uptake and tissue time-radioactivity curves that were most similar to [11C]flumazenil. In contrast, [18F]GEH120348 showed higher initial brain uptake but very different pharmacokinetics, with continued accumulation of radioactivity into the cortical regions of high GABA/benzodiazepine receptor concentrations and very little clearance from the regions of low receptor densities. Rapid washout of both radiotracers occurred upon treatment with unlabeled flumazenil. Conclusion The ease of the radiochemical synthesis, together with in vivo brain pharmacokinetics most similar to [11C]flumazenil, support that [18F]AH114726 is a suitable option for imaging the GABAA receptor.

Ex Vivo Tracing of NMDA and GABA-A Receptors in Rat Brain After Traumatic Brain Injury Using 18F-GE-179 and 18F-GE-194 Autoradiography

“…18 F-GE-179 and 18 F-GE-194 were synthetized at Turku PET Centre Radiopharmaceutical Laboratory, as described previously (15,18). The specific activity of tracers exceeded 1 TBq/mmol, and radiochemical purity was greater than 99% in all syntheses ( 18 F-GE-179, n 5 3; 18 F-GE-194, n 5 4).…”

“…A novel putative PET ligand, 18 F-GE-179, was recently introduced for the detection of NMDA ion-channel activity (15). 18 F-GE-179 has been shown to target the intrachannel phencyclidine binding site and therefore to selectively bind to the open/active state of NMDA receptor ion channels (16,17).…”

“…18 F-GE-179 has been shown to target the intrachannel phencyclidine binding site and therefore to selectively bind to the open/active state of NMDA receptor ion channels (16,17). Another novel PET ligand, 18 F-GE-194, was introduced for the detection of GABA-A receptors (18).…”

“…18 F-GE-179 has been shown to target the intrachannel phencyclidine binding site and therefore to selectively bind to the open/active state of NMDA receptor ion channels (16,17). Another novel PET ligand, 18 F-GE-194, was introduced for the detection of GABA-A receptors (18). 18 F-GE-194 is an 18 F-labeled tracer with properties comparable to those of 11 C-flumazenil, providing a longer half-life than those of 11 C-labeled tracers (19).…”

“…Another novel PET ligand, 18 F-GE-194, was introduced for the detection of GABA-A receptors (18). 18 F-GE-194 is an 18 F-labeled tracer with properties comparable to those of 11 C-flumazenil, providing a longer half-life than those of 11 C-labeled tracers (19).…”