Benzodiazepine Receptor Imaging Research Articles

Early [(11)C]Flumazenil/H(2)O positron emission tomography predicts irreversible ischemic cortical damage in stroke patients receiving acute thrombolytic therapy.

Central benzodiazepine receptor ligands, such as [(11)C]flumazenil (FMZ), are markers of neuronal integrity and therefore might be useful in the differentiation of functionally and morphologically damaged tissue early in ischemic stroke. We sought to assess the value of a benzodiazepine receptor ligand for the early identification of irreversible ischemic damage to cortical areas that cannot benefit from reperfusion. Eleven patients (7 male, 4 female, aged 52 to 75 years) with acute, hemispheric ischemic stroke were treated with alteplase (recombinant tissue plasminogen activator; 0.9 mg/kg according to National Institute of Neurological Disorders and Stroke protocol) within 3 hours of onset of symptoms. At the beginning of thrombolysis, cortical cerebral blood flow ([(15)O]H(2)O) and FMZ binding were assessed by positron emission tomography (PET). Those early PET findings were related to the change in neurological deficit (National Institutes of Health Stroke Scale) and to the extent of cortical damage on MRI or CT 3 weeks after the stroke. Hypoperfusion was observed in all cases, and in 8 patients the values were below critical thresholds estimated at 12 mL/100 g per minute, comprising 1 to 174 cm(3) of cortical tissue. Substantial reperfusion was seen in most of these regions 24 hours after thrombolysis. In 4 cases, distinct areas of decreased FMZ binding were detected. Those patients suffered permanent lesions in cortical areas corresponding to their FMZ defects (112 versus 146, 3 versus 3, 2 versus 1, and 128 versus 136 cm(3)). In the other patients no morphological defects were detected on MRI or CT, although blood flow was critically decreased in areas ranging in size up to 78 cm(3) before thrombolysis. These findings suggest that imaging of benzodiazepine receptors by FMZ PET distinguishes between irreversibly damaged and viable penumbra tissue early after acute stroke.

Benzodiazepine receptor imaging with iomazenil SPECT in aphasic patients with cerebral infarction.

To investigate the relationship between prognosis of aphasia and neuronal damage in the cerebral cortex, we evaluated the distribution of central-type benzodiazepine receptor (BZR) binding in post-stroke aphasics with [123I]iomazenil and SPECT. We performed iomazenil SPECT in six aphasic patients (aged from 45 to 75 years; all right-handed) with unilateral left cerebral infarction. Three patients showed signs of Broca's aphasia and the other three Wernicke's aphasia. Cerebral blood flow (CBF) imaging was performed with [123I]iodoamphetamine (IMP). The regions of interest (ROIs) on both images were set in the cerebral cortex, cerebellar cortex and language-relevant area in both hemispheres. Three patients were classified in the mild prognosis group and the other three in the moderate prognosis group. The left language-relevant area was more closely concerned with the difference in aphasic symptoms than the right one in both BZR and CBF distribution, but the ipsilateral to the contralateral ratio (I/C ratio) in the language-relevant areas in the BZR distribution was significantly lower in the moderate prognosis group than in the mild prognosis group, although no difference was seen for these values between the two groups in the CBF distribution. These results suggest that BZR imaging, which makes possible an increase in neuronal cell viability in the cerebral cortex, is useful not only for clarifying the aphasic symptoms but also for evaluating the prognosis of aphasia in patients with cerebral infarction.

Evaluation of neuronal loss in adult moyamoya disease by 123I-iomazenil SPECT

BACKGROUND Central benzodiazepine (BZD) receptor imaging is effective to evaluate neuron density in the pathological brain cortex. This study used BZD receptor imaging to evaluate neuronal damage in adult ischemic moyamoya disease. METHODS Single photon emission computed tomography and a novel tracer, 123I-iomazenil, were used to measure BZD receptor density in the brain. Evaluation of early and late images was performed in three asymptomatic, unoperated patients, and six mildly symptomatic, operated patients. RESULTS Uptakes in the frontal, parietal, and occipital lobes of symptomatic patients were significantly lower ( p < 0.05) than those of asymptomatic patients. The late image/early image count ratios (L/E ratios) of asymptomatic patients were relatively constant (mean, 0.571; range, 0.550–0.581) in all regions of interest. In contrast, the L/E ratios of symptomatic patients were not uniform. CONCLUSIONS The neuron density was preserved in adult asymptomatic patients despite harboring moyamoya disease. In contrast, the neuronal density was decreased in symptomatic patients even though their symptoms were mild and they had undergone revascularization.

Bromine-76 and carbon-11 labelled NNC 13-8199, metabolically stable benzodiazepine receptor agonists as radioligands for positron emission tomography.

NNC 13-8241 has recently been labelled with iodine-123 and developed as a metabolically stable benzodiazepine receptor ligand for single-photon emission computed tomography (SPECT) in monkeys and man. NNC 13-8199 is a bromo-analogue of NNC 13-8241. This partial agonist binds selectively and with subnanomolar affinity to the benzodiazepine receptors. We prepared 76Br labelled NNC 13-8199 from the trimethyltin precursor by the chloramine-T method. Carbon-11 labelled NNC 13-8199 was synthesised by N-alkylation of the nitrogen of the amide group with [11C]methyl iodide. Positron emission tomography (PET) examination with the two radioligands in monkeys demonstrated a high uptake of radioactivity in the occipital, temporal and frontal cortex. In the study with [76Br]NNC 13-8199, the monkey brain uptake continued to increase until the time of displacement with flumazenil at 215 min after injection. For both radioligands the radioactivity in the cortical brain regions was markedly reduced after displacement with flumazenil. More than 98% of the radioactivity in monkey plasma represented unchanged radioligand 40 min after injection. The low degree of metabolism indicates that NNC 13-8199 is metabolically much more stable than hitherto developed PET radioligands for imaging of benzodiazepine receptors in the primate brain. [76Br]NNC 13-8199 has potential as a radioligand in human PET studies using models where a slow metabolism is an advantage.

Significant reduction of seizure incidence and increase of benzodiazepine receptor density after interstitial radiosurgery in low-grade gliomas.

Epilepsy is the leading symptom in low grade gliomas. In order to evaluate the effect of interstitial radiosurgery on seizure incidence the authors retrospectively analysed the outcome of 80 patients with temporal grade-II astrocytomas and a history of epilepsy. Patients were treated by 125-iodine temporary implants using 60 Gy as reference dose. The dose rate was 9.6 +/- 1.6 cGy/h. Median follow-up was 4.1 years. In 20 patients benzodiazepine receptor imaging was performed using single photon emission computed tomography and iomazenil. Treatment with carbamazepine alone led to a significant reduction in seizure incidence with 28% of patients being seizure-free (p < 0.05). Interstitial radiosurgery led to a further reduction of seizures rendering 40% of patients seizure-free after 3 months. After 6 months only 21% of patients still had seizures that were refractory to medical treatment (p < 0.01). SPECT imaging revealed that all tumours had a significant reduction of benzodiazepine receptors which also applied to the surrounding brain. After interstitial radiosurgery of tumours, receptor density increased in brain adjacent to the tumour (0.68 to 0.94 ratio ipsi to contralateral brain, p < 0.01) coincident with significant tumour shrinkage. Thus, in epileptogenic temporal low grade gliomas, interstitial radiosurgery not only reduced the tumour burden but also effectively treated the concomitant epilepsy, resulting in 79% of patients being seizure-free after combined treatment by radiosurgery and anticonvulsive medication. These results compare favourably to the outcome after resection in lesional epilepsy raising the issue of radiosurgery as a less invasive alternative to open epilepsy surgery.

S.08.05 - PET imaging of benzodiazepine receptors and their relationship to anxiety disorders

S.08.05 - PET imaging of benzodiazepine receptors and their relationship to anxiety disorders

366 Benzodiazepine receptor imaging in Alzheimer's disease using 123-I labeled iomazenil, compared with cerebral blood flow and metabolism

366 Benzodiazepine receptor imaging in Alzheimer's disease using 123-I labeled iomazenil, compared with cerebral blood flow and metabolism

PS-28-2 Cortical benzodiazepine receptor imaging SPECT in 10 patients with temporal lobe epilepsy

PS-28-2 Cortical benzodiazepine receptor imaging SPECT in 10 patients with temporal lobe epilepsy

Central benzodiazepine receptor imaging and quantitation with single photon emission computerised tomography: SPECT

This review discusses the current use of single photon emission computerised tomography (SPECT) for central benzodiazepine receptor imaging and quantitation. The general principles underlying SPECT imaging and receptor quantitation methods such as the kinetic, pseudo-equilibrium and steady-state (tracer infusion and bolus) approaches are described. The advantages and practical drawbacks of these techniques are highlighted.

Transient increase in the in vivo binding of the benzodiazepine antagonist [3H]flumazenil in deafferented visual areas of the adult mouse brain.

Flumazenil is an imidazobenzodiazepine, an antagonist of central benzodiazepine (BDZ) receptors. BDZ binding sites are a modulatory component located on the gamma-aminobutyric acid (GABA) receptor macromolecule. We studied the effect of monocular enucleation on [3H]flumazenil binding in deprived and intact visual areas and nonvisual areas of the adult mouse brain under in vivo conditions. [3H]flumazenil binding was examined at seven time points up to 56 days postenucleation. In some monocularly deprived mice, changes in local blood flow accompanied with the BDZ receptor response were evaluated by coinjection of [3H]flumazenil and 99mTc-HMPAO. Monocular enucleation produced a transient increase in [3H]flumazenil binding in the deprived visual cortex and superior colliculus. At 17 days postenucleation, [3H]flumazenil binding in the anterior and posterior portions of the visual cortex and the superior colliculus increased by 28%, 15% and 23%, respectively, and declined to control levels at 45 days postenucleation. The increase in [3H]flumazenil was accompanied with a decrease in blood flow. Alterations in BDZ receptors and blood flow were selective to deprived visual structures. The regional correlation between the metabolic deficit and the BDZ response provides further support that the increase in BDZ receptor binding is confined to regions of reduced neuronal activity. [11C]flumazenil is an excellent radiotracer for in vivo imaging of benzodiazepine receptors in human brain using positron emission tomography (PET). This study suggests the suitability of [11C]flumazenil for in vivo PET study of BDZ receptor response to deafferentation of visual structures in human brain.

Comparison of benzodiazepine receptor and regional cerebral blood flow imaging of epileptiform foci in hippocampal kindled rabbits: A preliminary report

To clarify experimentally which of benzodiazepine (BZ) receptor or regional cerebral blood flow (rCBF) imaging is more sensitive in the detection of epileptic foci, we simultaneously examined the BZ receptor and rCBF distribution changes in hippocampal kindled rabbits with in vivo double tracer autoradiography using 125I-labeled Ro 16-0154 ( 125I-Iomazenil) and 99mTc-labeled hexamethyl-propyleneamine oxime ( 99mTc-HMPAO). In visual analysis of brain slices extracted after the intravenous injection of the double tracer following the kindling completion, 125I-Iomazenil accumulation was more markedly and extensively decreased in the kindled right CA1 region mimicking a primary epileptic focus than 99mTc-HMPAO accumulation. Further, this decrease in 125I-Iomazenil accumulation was not due to neuropathological abnormalities which consisted only of tissue damage corresponding to electrode track in the right CA1. These results suggest that BZ receptor imaging is more sensitive in the detection of epileptic foci than rCBF imaging and, therefore, that BZ receptor is useful in clinical epilepsy.

Comparison of benzodiazepine receptor and regional cerebral blood floq imaging of epileptiform foci in hippocampal kindled rabbits: a study with in vivo double tracer autoradiography using 125I-Iomazenil and 99mTc-HMPAO

To clarify experimentally whether benzodiazepine (Bz) receptor or regional cerebral blood flow (rCBF) imaging is more sensitive in the detection of epileptic foci, we simultaneously examined the Bz receptor and rCBF distribution changes in hippocampal kindled rabbits with in vivo double tracer autoradiography using 125I-labeled Ro 16-0154 ( 125I-Iomazenil) and 99mTc-labeled hexamethylpropylene amine oxime ( 99mTc-HMPAO). In visual and quantitative analyses, 125I-Iomazenil accumulation in brain slices extracted after the completion of the kindling was markedly and extensively decreased in the kindled right CA1 region, and further in the right temporal lobe, dentate gyrus, CA2, CA4, and bilateral CA3 regions, regarded as the propagated sites of seizure discharges. 99mTc-HMPAO accumulation was much more slightly and less extensively decreased in the right CA1, frontal, temporal and dentate gyri. Further, this decrease in 125I-Iomazenil accumulation was not due to neuropathological abnormalities, which consisyed only of tissue damage corresponding to electrode track in the CA1. Both the kindled and propagated sites are known to have possibility of acquiring epileptogenesis as experimental epileptic foci. These results suggest that Bz receptor imaging is much more sensitive in the detection of epileptic foci than rCBF imaging, and therefore that Bz receptor imaging is useful in clinical epilepsy.

Imaging benzodiazepine receptors in the human brain by single photon emission computed tomography (SPECT)

Recently, [ 123I]Ro16-0154 has been introduced as a potential benzodiazepine (BZD) receptor imaging tracer for SPECT. We investigated the biodistribution of [ 123I]Ro16-0154 in humans and compared it with the animal data. There was a rapid and high 123I-uptake in the brain comparable to rCBF. In the following images, however, regionally different changes were observed, resulting in a subsequent intracerebral retention parallel to the known distribution of BZD receptors. The results suggest that [ 123I]Ro16-0154 is of potential clinical use as a BZD receptor imaging agent.