Synthesis of ethyl 8-fluoro-5,6-dihydro5- [11C]methyl-6-oxo-4H-imidazo[1,5-a] [1,4]benzodiazepine-3-carboxylate (RO 15.1788-11C): A specific radioligand for the in vivo study of central benzodiazepine receptors by positron emission tomography

doi:10.1016/0020-708X(84)90215-1

The International Journal of Applied Radiation and Isotopes

Volume 35, Issue 10, October 1984, Pages 973-976

https://doi.org/10.1016/0020-708X(84)90215-1 Get rights and content

Abstract

A method of labelling ethyl 8-fluoro-5,6-dihydro-5-[¹¹C]methyl-6-oxo-4H-imidazo[1,5-a][1,4]benzodiazepine-3-carboxylate (RO 15.1788 ¹¹C), a benzodiazepine antagonist with carbon-11 has been developed. RO 15.1788-¹¹C was prepared by methylation of the nor derivative by I¹¹CH₃. About 100 mCi (maximum 153 mCi, 5.66 GBq) of the chemically and radiochemically pure labelled product were obtained within 25 min with a specific activity on average of 1100 mCi/μmol (maximum 1740 mCi/μmol– 64.4 GBq/μmol). Preliminary results obtained after i.v. administration in the baboon have shown RO 15.1788-¹¹C to be of interest as a benzodiazepine radioligand for the in vivo study of benzodiazepine receptors by positron emission tomography.

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The chemistry of labeling heterocycles with carbon-11 or fluorine-18 for biomedical imaging
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Use of this method of [11C]formaldehyde synthesis gave moderate molar activity. A secondary amido nitrogen in a benzodiazepine (1984ARI973, 1988ARI993, 1992PSYP16, 2007JLCR19) can be methylated with [11C]methyl iodide under basic conditions, as in the synthesis of [11C]flumazenil ([11C]5), a prominent central benzodiazepine receptor radioligand, from amide 328 (Scheme 102) (1988ARI993). Various techniques have been developed for performing such 11C-N-alkylations efficiently, including use of the loop method and of captive solvents (2007JLCR19).
Over the last half-century, the molecular imaging technique of positron emission tomography (PET) has emerged as an important tool for biomedical research, drug development and medical diagnosis. The power of PET derives from its utilization of radiotracers that can report specific information on pharmacology, biochemistry, and physiology. Many of these radiotracers are heterocycles that have been labeled with a short-lived cyclotron-produced radioisotope, either carbon-11 (t_1/2 = 20.4 min) or fluorine-18 (t_1/2 = 109.8 min). This review addresses the chemical challenges to be met in producing PET radiotracers with these radioisotope labels at heterocyclic moieties and the methods now available for doing so.
Automated radiosynthesis and purification of [18F]flumazenil with solid phase extraction
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It has also been used to examine patients with disorders such as Alzheimer's disease, degenerative disorders of the basal ganglia and cerebellum, ischemic stroke (Heiss et al., 2007) and to support drug development (Declercq et al., 2016). Flumazenil labeled with carbon-11 ([11C]FMZ) was the first radioligand for PET imaging of the GABAA system (Mazière et al., 1984) and the gold reference for GABAA receptors evaluation, but short half-life of carbon-11 (T1/2 = 20.4 min) imposes requirements upon the duration of the radiochemical synthesis and following PET study. Application of relatively long-lived isotope, fluorine-18 (T1/2 = 109.8 min) allows overcoming these limitations.
This paper describes the novel approach for preparation of [¹⁸F]flumazenil ([¹⁸F]FMZ), well known radioligand for assessment of GABA_A receptors by PET. The optimized reaction conditions allowed us to implement commercially available SPE cartridges for [¹⁸F]FMZ purification avoiding HPLC. All procedures were performed with TRACERlab FX N Pro synthesizer in 53 min. Developed approach provided [¹⁸F]FMZ with high RCP (> 97%) and low level of chemical impurities (< 5 µg/mL). FMZ was routinely synthesized in 6.4 ± 0.7% RCY at EOS (not decay corrected, n = 8) and the molar radioactivity was > 185 GBq/μmol.
Advanced [18F]FDG and [11C]flumazenil PET analysis for individual outcome prediction after temporal lobe epilepsy surgery for hippocampal sclerosis
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Citation Excerpt :
A 68Ge transmission scan was acquired for attenuation correction. FMZ (RO 15-1788) was radiolabelled with 11C via methylation (Maziere et al., 1984). Unlabelled FMZ (0.01 mg/kg) and [11C]FMZ (2.775 MBq/kg) were injected simultaneously (Delforge et al., 1995), and twelve frames of increasing length were acquired over 55 min (for details, see (Yankam Njiwa et al., 2013)).
We have previously shown that an imaging marker, increased periventricular [¹¹C]flumazenil ([¹¹C]FMZ) binding, is associated with failure to become seizure free (SF) after surgery for temporal lobe epilepsy (TLE) with hippocampal sclerosis (HS). Here, we investigated whether increased preoperative periventricular white matter (WM) signal can be detected on clinical [¹⁸F]FDG-PET images. We then explored the potential of periventricular FDG WM increases, as well as whole-brain [¹¹C]FMZ and [¹⁸F]FDG images analysed with random forest classifiers, for predicting surgery outcome.
Sixteen patients with MRI-defined HS had preoperative [¹⁸F]FDG and [¹¹C]FMZ-PET. Fifty controls had [¹⁸F]FDG-PET (30), [¹¹C]FMZ-PET (41), or both (21). Periventricular WM signal was analysed using Statistical Parametric Mapping (SPM8), and whole-brain image classification was performed using random forests implemented in R (http://www.r-project.org). Surgery outcome was predicted at the group and individual levels.
At the group level, non-seizure free (NSF) versus SF patients had periventricular increases with both tracers. Against controls, NSF patients showed more prominent periventricular [¹¹C]FMZ and [¹⁸F]FDG signal increases than SF patients. All differences were more marked for [¹¹C]FMZ. For individuals, periventricular WM signal increases were seen at optimized thresholds in 5/8 NSF patients for both tracers. For SF patients, 1/8 showed periventricular signal increases for [¹¹C]FMZ, and 4/8 for [¹⁸F]FDG. Hence, [¹⁸F]FDG had relatively poor sensitivity and specificity. Random forest classification accurately identified 7/8 SF and 7/8 NSF patients using [¹¹C]FMZ images, but only 4/8 SF and 6/8 NSF patients with [¹⁸F]FDG.
This study extends the association between periventricular WM increases and NSF outcome to clinical [¹⁸F]FDG-PET, but only at the group level. Whole-brain random forest classification increases [¹¹C]FMZ-PET's performance for predicting surgery outcome.
The development of potential new fluorine-18 labelled radiotracers for imaging the GABA<inf>A</inf> receptor
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Positron emission tomography (PET) using the tracer [¹¹C]Flumazenil has shown changes in the distribution and expression of the GABA_A receptor in a range of neurological conditions and injury states. We aim to develop a fluorine-18 labelled PET agent with comparable properties to [¹¹C]Flumazenil. In this study we make a direct comparison between the currently known fluorine-18 labelled GABA_A radiotracers and novel imidazobenzodiazepine ligands. A focussed library of novel compound was designed and synthesised where the fluorine containing moiety and the position of attachment is varied. The in vitro affinity of twenty-two compounds for the GABA_A receptor was measured. Compounds containing a fluoroalkyl amide or a longer chain ester group were eliminated due to low potency. The fluorine-18 radiochemistry of one compound from each structural type was assessed to confirm that an automated radiosynthesis in good yield was feasible. Eleven of the novel compounds assessed appeared suitable for in vivo assessment as PET tracers.
Periventricular 11Cflumazenil binding for predicting postoperative outcome in individual patients with temporal lobe epilepsy and hippocampal sclerosis
2013, NeuroImage: Clinical
Citation Excerpt :
Written informed consent had been signed by control subjects at the time of PET scanning in agreement with the French legislation and after approval by the local Ethics committee. FMZ (RO15-1788) was radiolabeled with 11C using methylation (Maziere et al., 1984). PET scans were acquired using an Exact ECAT HR + scanner (Siemens, Erlangen, Germany) in the high sensitivity three-dimensional mode with a spatial resolution of about 5 mm full with half maximum (FWHM) measured with 18F according to the NEMA protocol (Brix et al., 1997).
A third of patients with intractable temporal lobe epilepsy and hippocampal sclerosis (HS) are not seizure free (NSF) after surgery. Increased periventricular [¹¹C]flumazenil (FMZ) binding, reflecting heterotopic neuron concentration, has been described as one predictor of NSF outcome at the group level. We aimed to replicate this finding in an independent larger cohort and investigated whether NSF outcome can be predicted in individuals.
Preoperative [¹¹C]FMZ summed radioactivity images were available for 16 patients with HS and 41 controls. Images were analyzed using SPM8, explicitly including the white matter, and correction for global radioactivity via group-specific ANCOVA. Periventricular increases were assessed with a mask and different cutoffs for distinguishing NSF and seizure free (SF) patients.
NSF patients had increased [¹¹C]FMZ binding around the posterior horn of the ventricles ipsilaterally (z = 2.53) and contralaterally (z = 4.44) to the seizure focus compared with SF patients. Compared with controls, SF patients had fewer periventricular increases (two clusters, total volume 0.87 cm³, z_max = 3.8) than NSF patients (two ipsilateral and three contralateral clusters, 6.15 cm³, z_max = 4.8). In individuals and at optimized cutoffs, five (63%) of eight NSF patients and one (13%) of eight SF patients showed periventricular increases compared with controls (accuracy 75%). Only one (2%) of the 41 controls had increases at the same cutoff.
The association between periventricular [¹¹C]FMZ increases and NSF outcome after temporal lobe resection for HS has been confirmed in an independent cohort on simple summed activity images. [¹¹C]FMZ-PET may be useful for individual preoperative counseling with clinically relevant accuracy.
Gaba and serotonin molecular neuroimaging in essential tremor: A clinical correlation study
2012, Parkinsonism and Related Disorders
Essential tremor is the most common movement disorder in adults, but its exact etiology and pathophysiology are still not fully understood. There is some consensus, however, about the involvement of the cerebellum and accumulating evidence points towards a dysfunction of the gabaergic system. We hypothesize that the serotonin neurotransmission system may also play a role as it does in tremor in Parkinson disease. This study aimed to investigate the association between the severity of tremor symptoms and the gabaergic and serotoninergic neurotransmission systems in essential tremor.
We measured the tremor clinical rating scale score and acquired DASB and Flumazenil PET scans in 10 patients who presented with essential tremor at different stages of clinical severity. Statistically significant correlations were sought between the scale scores and parametric binding potential images.
The correlation analysis of cerebellar Flumazenil uptake and tremor clinical rating scale scores reached statistical significance (R2 = 0.423, p = 0.041), whereas no association was detected in the DASB scans.
The severity of tremor correlated with the abnormalities found in GABA receptor binding, suggesting a primary gabaergic deficiency or a functional abnormality at the level of GABA_A receptor subtypes. These results may assist in the rational development of new pharmacological treatments for essential tremor.

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The International Journal of Applied Radiation and Isotopes

Abstract

References (14)

Life Sci.

Int. J. Appl. Radiat. Isot.

Naunyn Schmiedebergs Arch. Pharmac.

Nature

Nature

Cited by (164)

The chemistry of labeling heterocycles with carbon-11 or fluorine-18 for biomedical imaging

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Advanced [<sup>18</sup>F]FDG and [<sup>11</sup>C]flumazenil PET analysis for individual outcome prediction after temporal lobe epilepsy surgery for hippocampal sclerosis

The development of potential new fluorine-18 labelled radiotracers for imaging the GABA<inf>A</inf> receptor

Periventricular <sup>11</sup>Cflumazenil binding for predicting postoperative outcome in individual patients with temporal lobe epilepsy and hippocampal sclerosis

Gaba and serotonin molecular neuroimaging in essential tremor: A clinical correlation study