Synthesis and in vitro evaluation of 18F-labelled S-fluoroalkyl diarylguanidines: Novel high-affinity NMDA receptor antagonists for imaging with PET

Robins, Edward G.; Zhao, Yongjun; Khan, Imtiaz Ahmed; Wilson, Anthony; Luthra, Sajinder K.; Årstad, Erik

doi:10.1016/j.bmcl.2010.01.052

Cited by 40 publications

(62 citation statements)

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“…The demographic and descriptive data for the subjects are presented in Table 1. 18 F-GE-179 was synthesized by Hammersmith Imanet Limited as previously described (11). Details of the injectate are presented in Table 1.…”

Section: Methodsmentioning

confidence: 99%

“…GE-179 has a distribution coefficient (log D 7.4 ) of 2.49 6 0.1 (11), similar to that of CNS 5161 (log P 5 1.92 6 0.26 (13)) and indicative of moderate lipophilicity. In a binding study to characterize GE-179 binding to CNS targets other than the NMDA phencyclidine site, 10 nM GE-179 did not significantly bind to any of the 60 receptors, channels, and transporters assessed.…”

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confidence: 92%

“…In vitro evaluation of a 18 F-labeled analog of CNS 5161 ( 18 F-GE-179 (11)) showed that 18 F-GE-179 displaces 3 H-TCP (-3 H-N-(1-[thienyl] cyclohexyl)piperidine) from the phencyclidine site with a Ki (inhibition constant) of 2.4 nM (similar to that seen with 3 H-MK-801 ( 3 H-(1)-5-methyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5,10-imine maleate) and CNS 5161 (12)) and GE-179 inhibits glutamate-mediated influx of Ca 21 in teratocarcinoma 2 (NT2) cells differentiated to express human NMDA receptors in a dose-dependent manner (supplemental data; supplemental mate-rials are available at http://jnm.snmjournals.org). GE-179 has a distribution coefficient (log D 7.4 ) of 2.49 6 0.1 (11), similar to that of CNS 5161 (log P 5 1.92 6 0.26 (13)) and indicative of moderate lipophilicity.…”

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confidence: 99%

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Initial Evaluation of ¹⁸F-GE-179, a Putative PET Tracer for Activated N-Methyl d-Aspartate Receptors

et al. 2014

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and 6 GE Healthcare plc, Amersham, United Kingdom N-methyl D-aspartate (NMDA) ion channels play a key role in a wide range of physiologic (e.g., memory and learning tasks) and pathologic processes (e.g., excitotoxicity). To date, suitable PET markers of NMDA ion channel activity have not been available. 18 F-GE-179 is a novel radioligand that selectively binds to the open/active state of the NMDA receptor ion channel, displacing the binding of 3 H-tenocyclidine from the intrachannel binding site with an affinity of 2.4 nM. No significant binding was observed with 10 nM GE-179 at 60 other neuroreceptors, channels, or transporters. We describe the kinetic behavior of the radioligand in vivo in humans. Methods: Nine healthy participants (6 men, 3 women; median age, 37 y) each underwent a 90-min PET scan after an intravenous injection of 18 F-GE-179. Continuous arterial blood sampling over the first 15 min was followed by discrete blood sampling over the duration of the scan. Brain radioactivity (KBq/mL) was measured in summation images created from the attenuation-and motion-corrected dynamic images. Metabolite-corrected parent plasma input functions were generated. We assessed the abilities of 1-, 2-, and 3-compartment models to kinetically describe cerebral time-activity curves using 6 bilateral regions of interest. Parametric volume-of-distribution (V T ) images were generated by voxelwise rank-shaping regularization of exponential spectral analysis (RS-ESA). Results: A 2-brain-compartment, 4-rate-constant model best described the radioligand's kinetics in normal gray matter of subjects at rest. At 30 min after injection, 37% of plasma radioactivity represented unmetabolized 18 F-GE-179. The highest mean levels of gray matter radioactivity were seen in the putamina and peaked at 7.5 min. A significant positive correlation was observed between K 1 and V T (Spearman ρ 5 0.398; P 5 0.003). Between-subject coefficients of variation of V T ranged between 12% and 16%. Voxelwise RS-ESA yielded similar V T s and coefficients of variation. Conclusion: 18 F-GE-179 exhibits high and rapid brain extraction, with a relatively homogeneous distribution in gray matter and acceptable between-subject variability. Despite its rapid peripheral metabolism, quantification of 18 F-GE-179 V T is feasible both within regions of interest and at the voxel level. The specificity of 18 F-GE-179 binding, however, requires further characterization with in vivo studies using activation and disease models.

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Section: Methodsmentioning

confidence: 99%

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confidence: 92%

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Initial Evaluation of ¹⁸F-GE-179, a Putative PET Tracer for Activated N-Methyl d-Aspartate Receptors

et al. 2014

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“…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).…”

Section: Synthesis Of 18 F-ge-179 and 18 F-ge-194mentioning

confidence: 99%

“…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).…”

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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

et al. 2016

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In vivo imaging of N-methyl-D-aspartate (NMDA) glutamate receptor and γ-aminobutyric acid (GABA)-A receptor during progression of brain pathology is challenging because of the lack of imaging tracers with high affinity and specificity. Methods: We monitored changes in NMDA receptor and GABA-A receptor in a clinically relevant model of traumatic brain injury (TBI) induced by lateral fluid percussion in adult rats, using 2 new ligands for PET: 18 F-GE-179 for the open/active state of the NMDA receptor ion channel and 18 F-GE-194 for GABA-A receptor. Ex vivo brain autoradiography of radioligands was performed at subacute (5-6 d) and chronic (40-42 d) time points after TBI. Results: At 5-6 d after TBI, 18 F-GE-179 binding was higher in the cortical lesion area, in the lesion core, and in the hippocampus than in the corresponding contralateral regions; this increase was probably related to increased permeability of the blood-brain barrier. At 40-42 d after TBI, 18 F-GE-179 binding was significantly higher in the medial cortex, in the corpus callosum, and in the thalamus than in the corresponding contralateral regions. Five to 6 days after TBI, 18 F-GE-194 binding was significantly higher in the lesion core and significantly lower in the ipsilateral thalamus. By 40-42 d after TBI, the reduction in 18 F-GE-194 binding extended to the cortical lesion, including the perilesional cortex around the lesion core. The reduction in thalamic binding was more extensive at 40-42 d than at 5-6 d after TBI, suggesting a progressive decrease in thalamic GABA-A receptor density. Immunohistochemistry against GABA-A α1 subunit revealed a similar decrease to 18 F-GE-194 binding, particularly during the chronic phase. Conclusion: Our data support the validity of novel 18 F-GE-179 and 18 F-GE-194 radioligands for the detection of changes in active NMDA receptor and GABA-A receptor in the injured brain. These tools are useful for follow-up evaluation of secondary postinjury pathologies.

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

Sobrio

2013

Labelled Comp Radiopharmac

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l-Glutamate is the major neurotransmitter in the central nervous system and activates both ionotropic and metabotropic receptors. Here the radiosynthesis of radiotracers developed for both types of receptors are reviewed with a highlight on the radiopharmaceuticals used or evaluated in humans. At first, radiotracers were developed for ionotropic N-methyl-d-aspartate receptors without any success to obtain radiopharmaceuticals useable for clinical or even preclinical positron emission tomography (PET) imaging purposes. Some compounds were radiolabelled and evaluated for α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors without any successful results. The recent development of radiotracers for metabotropic glutamate receptors was more efficient because radiopharmaceuticals are currently evaluated or used in clinical trials to study the mGluR1, mGluR2 or mGluR5 receptors by PET. Although the majority of the radiotracers were classically labelled with carbon-11 by O- or N-[(11) C]-methylation or with fluorine-18 nucleophilic substitution of aromatic nitro or halogeno precursors using krypofix 2.2.2/potassium [(18) F]fluoride complex, some radiosyntheses were performed with recent radiolabelling reactions like the use of iodionium salt for [(18) F]-labelling.

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Synthesis and in vitro evaluation of 18F-labelled S-fluoroalkyl diarylguanidines: Novel high-affinity NMDA receptor antagonists for imaging with PET

Cited by 40 publications

References 34 publications

Initial Evaluation of ¹⁸F-GE-179, a Putative PET Tracer for Activated N-Methyl d-Aspartate Receptors

Initial Evaluation of ¹⁸F-GE-179, a Putative PET Tracer for Activated N-Methyl d-Aspartate Receptors

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

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

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Synthesis and in vitro evaluation of 18F-labelled S-fluoroalkyl diarylguanidines: Novel high-affinity NMDA receptor antagonists for imaging with PET

Cited by 40 publications

References 34 publications

Initial Evaluation of 18F-GE-179, a Putative PET Tracer for Activated N-Methyl d-Aspartate Receptors

Initial Evaluation of 18F-GE-179, a Putative PET Tracer for Activated N-Methyl d-Aspartate Receptors

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

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

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Product

Resources

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Initial Evaluation of ¹⁸F-GE-179, a Putative PET Tracer for Activated N-Methyl d-Aspartate Receptors

Initial Evaluation of ¹⁸F-GE-179, a Putative PET Tracer for Activated N-Methyl d-Aspartate Receptors

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