BACKGROUNDN,N-di-n-propyl-2-[2-(4-[¹¹C]methoxyphenyl)-6,8-dichloroimidazol[1,2-a]pyridine-3-yl]acetamide ([¹¹C]CB184) is a novel selective radioligand for the 18-kD translocator protein (TSPO), which is upregulated in activated microglia in the brain, and may be useful in positron emission tomography (PET). We examined the safety, radiation dosimetry, and initial brain imaging with [¹¹C]CB184 in healthy human volunteers.RESULTSDynamic [¹¹C]CB184 PET scans (90 min) were performed in five healthy male subjects. During the scan, arterial blood was sampled at various time intervals, and the fraction of the parent compound in plasma was determined with high-performance liquid chromatography. No serious adverse events occurred in any of the subjects throughout the study period. [¹¹C]CB184 was metabolized in the periphery: 36.7% ± 5.7% of the radioactivity in plasma was detected as the unchanged form after 60 min. The total distribution volume (V _T) was estimated with a two-tissue compartment model. The V _T of [¹¹C]CB184 was highest in the thalamus (5.1 ± 0.4), followed by the cerebellar cortex (4.4 ± 0.2), and others. Although regional differences were small, the observed [¹¹C]CB184 binding pattern was consistent with the TSPO distribution in the normal human brain. Radiation dosimetry was determined in three healthy male subjects using a serial whole-body PET scan acquired over 2 h after [¹¹C]CB184 injection. [¹¹C]CB184 PET demonstrated high uptake in the gallbladder at a later time (>60 min). In urine obtained approximately 100 min post-injection, 0.3% of the total injected radioactivity was recovered, indicating hepatobiliary excretion of radioactivity. The absorbed dose (μGy/MBq) was highest in the kidneys (21.0 ± 0.5) followed by the lungs (16.8 ± 2.7), spleen (16.6 ± 6.6), and pancreas (16.5 ± 2.2). The estimated effective dose for [¹¹C]CB184 was 5.9 ± 0.6 μSv/MBq.CONCLUSIONSThis initial evaluation indicated that [¹¹C]CB184 is feasible for imaging of TSPO in the brain.

2016-10-01·Annals of Nuclear Medicine

Preclinical and first-in-man studies of [11C]CB184 for imaging the 18-kDa translocator protein by positron emission tomography

Article

作者: Ishii, Kenji ; Ishiwata, Kiichi ; Endo, Shogo ; Ishibashi, Kenji ; Wagatsuma, Kei ; Toyohara, Jun ; Yanai, Shuichi ; Sakata, Muneyuki ; Hatano, Kentaro

OBJECTIVEWe performed preclinical and first-in-man clinical positron emission tomography (PET) studies in human brain using N,N-di-n-propyl-2-[2-(4-[(11)C]methoxyphenyl)-6,8-dichloroimidazol[1,2-a]pyridine-3-yl]acetamide ([(11)C]CB184) to image the 18-kDa translocator protein (TSPO), which is overexpressed in activated microglia in neuroinflammatory conditions.METHODSIn vitro selectivity of CB184 was characterized. The radiation absorbed dose by [(11)C]CB184 in humans was calculated from murine distribution data. Acute toxicity of CB184 hydrochloride in rats at a dose of 5.81 mg/kg body weight, which is >10,000-fold higher than the clinical equivalent dose of [(11)C]CB184, was evaluated. Acute toxicity of [(11)C]CB184 injection of a 400-fold dose to administer a postulated dose of 740 MBq [(11)C]CB184 was also evaluated after the decay-out of (11)C. The mutagenicity of CB184 was studied with a reverse mutation test (Ames test). The pharmacological effect of CB184 injection in mice was studied with an open field test. The first PET imaging of TSPO with [(11)C]CB184 in a normal human volunteer was performed.RESULTSA suitable preparation method for [(11)C]CB184 injection was established. CB184 showed low activity in a 28-standard receptor binding profile. The radiation absorbed dose by [(11)C]CB184 in humans was sufficiently low for clinical use, and no acute toxicity of CB184 or [(11)C]CB184 injection was found. No mutagenicity or apparent effect on locomotor activity or anxiety status was observed for CB184. We safely performed brain imaging with PET following administration of [(11)C]CB184 in a normal human volunteer. A 90-min dynamic scan showed rapid initial uptake of radioactivity in the brain followed by prompt clearance. [(11)C]CB184 was homogeneously distributed in the gray matter. The total distribution volume of [(11)C]CB184 was highest in the thalamus followed by the cerebellar cortex and elsewhere. Although regional differences were small, the observed [(11)C]CB184 binding pattern was consistent with the TSPO distribution in normal human brain. Peripherally, [(11)C]CB184 was metabolized in humans: 30 % of the radioactivity in plasma was detected as the unchanged form after 60 min.CONCLUSIONS[(11)C]CB184 is suitable for imaging TSPO in human brain and provides an acceptable radiation dose. Pharmacological safety was noted at the dose required for PET imaging.

2015-06-01·European Journal of Nuclear Medicine and Molecular Imaging1区 · 医学

Evaluation of [11C]CB184 for imaging and quantification of TSPO overexpression in a rat model of herpes encephalitis

1区 · 医学

Article

作者: Hatano, Kentaro ; Doorduin, Janine ; Toyohara, Jun ; de Vries, Erik F. J. ; Vallez Garcia, David ; Dierckx, Rudi A. J. O. ; Ishiwata, Kiichi

PURPOSEEvaluation of translocator protein (TSPO) overexpression is considered an attractive research tool for monitoring neuroinflammation in several neurological and psychiatric disorders. [(11)C]PK11195 PET imaging has been widely used for this purpose. However, it has a low sensitivity and a poor signal-to-noise ratio. For these reasons, [(11)C]CB184 was evaluated as a potentially more sensitive PET tracer.METHODSA model of herpes simplex encephalitis (HSE) was induced in male Wistar rats. On day 6 or 7 after virus inoculation, [(11)C]CB184 PET scans were acquired followed by ex vivo evaluation of biodistribution. In addition, [(11)C]CB184 and [(11)C]PK11195 PET scans with arterial blood sampling were acquired to generate input for pharmacokinetic modelling. Differences between the saline-treated control group and the virus-treated HSE group were explored using volumes of interest and voxel-based analysis.RESULTSThe biodistribution study showed significantly higher [(11)C]CB184 uptake in the amygdala, olfactory bulb, medulla, pons and striatum (p < 0.05) in HSE rats than in control rats, and the voxel-based analysis showed higher bilateral uptake in the pons and medulla (p < 0.05, corrected at the cluster level). A high correlation was found between tracer uptake in the biodistribution study and on the PET scans (p < 0.001, r (2) = 0.71). Pretreatment with 5 mg/kg of unlabelled PK11195 effectively reduced (p < 0.001) [(11)C]CB184 uptake in the whole brain. Both, [(11)C]CB184 and [(11)C]PK11195, showed similar amounts of metabolites in plasma, and the binding potential (BPND) was not significantly different between the HSE rats and the control rats. In HSE rats BPND for [(11)C]CB184 was significantly higher (p < 0.05) in the amygdala, hypothalamus, medulla, pons and septum than in control rats, whereas higher uptake of [(11)C]PK11195 was only detected in the medulla.CONCLUSION[(11)C]CB184 showed nonspecific binding to healthy tissue comparable to that observed for [(11)C]PK11195, but it displayed significantly higher specific binding in those brain regions affected by the HSE. Our results suggest that [(11)C]CB184 PET is a good alternative for imaging of neuroinflammatory processes.

100 项与 11C-CB-184 相关的药物交易

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