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N-Benzyl-N-ethyl -2-(7-[11C]-methyl-8-oxo-2-phenyl-7,8-dihydro-9H-purin-9-yl)acetamide


, MS and , PhD.

Author Information

Created: ; Last Update: December 31, 2007.

Chemical name:N-Benzyl-N-ethyl-2-(7-[11C]-methyl-8-oxo-2-phenyl-7,8-dihydro-9H-purin-9-yl)acetamideimage 46484599 in the ncbi pubchem database
Abbreviated name:[11C]AC-5216
Agent Category:Compound
Target:Peripheral-type benzodiazepine receptor (PBR, TSPO)
Target Category:Receptor binding
Method of detection:Positron Emission Tomography (PET)
Source of signal:11C
  • Checkbox In vitro
  • Checkbox Rodents
  • Checkbox Non-human primates
Click on the above structure for additional information in PubChem.



Peripheral-type benzodiazepine receptor (PBR, TSPO), which was initially found in peripheral organs such as the kidney, nasal epithelium, lung, heart, and endocrine organs (i.e., the adrenal, testis, and pituitary glands) was subsequently found in the central nervous system (CNS) (1). PBR is mainly located in the glial cells of the brain, and PBR expression in vivo was increased in microglia activated by brain injury (1). The increase of PBR density has thus been used as an indicator of neuronal damage and neurodegenerative disorders such as Alzheimer’s disease (1).

PBR has been studied with in vivo positron emission tomography (PET) using [11C]PK11195. However, the relatively low uptake of [11C]PK11195 into the brain limited its wide application. To characterize PBR precisely using a PET ligand with improved behaviors compared to [11C]PK11195, [11C]DAA1106 (2) and [18F]FEDAA1106 (3) were developed for PBR imaging in the brain. In vivo study demonstrated that they had higher uptakes and better specific binding in rodent and primate brains than [11C]PK11195 (2, 3). Now, [11C]DAA1106 and [18F]FEDAA1106 are used to investigate PBR in the human brain to elucidate the relationship between PBR and brain diseases (4, 5). Subsequently, [11C]PBR28 and [11C]PBR06 (6), two analogs of [11C]DAA1106, were developed to localize and qualify upregulated PBR associated with cerebral ischemia in rats.

N-Benzyl-N-ethyl-2-(7,8-dihydro-7-methyl-8-oxo-2-phenyl-9H-purin-9-yl)acetamide (AC-5216) was found to be a selective agonist for studying PBR in the central nervous system (7). AC-5216 had higher affinity for PBR prepared from rat brain than PK11195. AC-5216 also exhibited negligible activity for central benzodiazepine receptors (CBR) and a large number of other receptors, monoamine transporters, and ion channels. Moreover, the binding site of AC-5216 in the PBR domain might be closer to that of PK11195 than those of other PBR ligands. AC-5216 labeled with 11C ([11C]AC-5216) is being developed as a potent PET agent for the non-invasive study of microglia and macrophage activation relative to PBR in the brain (8-10).



Zhang et al. (8) synthesized [11C]AC-5216 by N-11C-methylation of the desmethyl precursor (N-benzyl-N-ethyl-2-(7,8-dihydro-8-oxo-2-phenyl-9H-purin-9-yl)acetamide) with [11C]CH3I in the presence of NaH. Subsequent high-performance liquid chromatography separation produced [11C]AC-5216 with a radiochemical purity ≥98% and a total synthesis time of 22 min. The specific activity was 85–130 GBq/μmol (2.3–3.5 Ci/μmol) at the end of synthesis. A reproducible radiochemical yield of 46% (decay-corrected) was reported.

In Vitro Studies: Testing in Cells and Tissues


In vitro [3H]PK11195 PBR-binding studies using rat brain mitochondrial homogenates showed inhibition constant values of 0.297 ± 0.009 nM and 0.602 ± 0.046 nM for AC-5216 and PK11195, respectively (8). Moreover, AC-5216 exhibited negligible affinity for CBR and a large number of other receptors, monoamine transporters, and ion channels. Autoradiography of rat brain slices revealed that [11C]AC-5216 had the highest radioactivity in choroid plexus, followed by the olfactory bulb and the cerebellum (9). This pattern of [11C]AC-5216 binding was similar to those of [11C]DAA1106 and [18F]FEDAA1106.

Animal Studies



Zhang et al. (8) reported that biodistribution studies in normal mice showed high accumulation of radioactivity in the lung, followed by the heart, kidney, and adrenal gland. The regional distribution in the mouse brain showed rapid penetration across the blood–brain barrier into all brain regions at 1 min after injection. Uptake in the olfactory bulb and cerebellum was >1.3% injected dose per gram (ID/g) at 5 min after injection. Radioactivity accumulated with time in these two regions, and the level peaked at 15 min and then declined until 60 min after injection. The highest radioactivity of [11C]AC-5216 (2.5% ID/g at 15 min) was found in the olfactory bulb, and moderate radioactivity (1.5% ID/g at 15 min) was also detected in the cerebellum; however, low uptake was found in other regions, such as the cerebral cortex and striatum. Coinjection of non-radioactive AC-5216 or PK11195 decreased the accumulation in all brain regions, with the most significant reduction in the olfactory bulb and cerebellum. In contrast, CBR-selective flumazenil or Ro15-4513 coinjection did not have a clear inhibitory effect on the uptake of [11C]AC-5216. Almost all of the [11C]AC-5216 radioactivity in the brain was unchanged at 60 min after injection.

Yanamoto et al. (9) reported that autoradiographic studies of [11C]AC-5216 showed brain binding in rat striatum lesions induced by kainic acid (KA). The binding of [11C]AC-5216 in the KA-lesioned striatum was two- to three-fold higher than that in the control striatum. Treatment with a large amount of non-radioactive AC-5216 or PK11195 inhibited the binding of [11C]AC-5216 and diminished the difference of radioactivity levels between the lesion and non-lesioned sides. These results demonstrated that [11C]AC-5216 had high specific binding to PBR in the KA-lesioned rat brain.

Amitani et al. (10) investigated the intratumoral distribution of [11C]AC-5216 in mice bearing fibrosarcomas. In the fibrosarcomas, [11C]AC-5216 was rapidly incorporated into tumor tissues at relatively high concentrations, and the uptake increased gradually with time (to ~4% ID/g). In ex vivo autoradiograms, [11C]AC-5216 uptake in the fibrosarcomas was rather heterogeneous. In contrast, in in vitro autoradiograms, intratumoral distribution was almost homogeneous throughout the tumors. Furthermore, the regional distribution of [11C]AC-5216 uptake in the fibrosarcomas was similar to the uptake of 14C-labeled iodoantipyrine.

Other Non-Primate Mammals


No publication is currently available.

Non-Human Primates


Zhang et al. (8) reported PET studies of [11C]AC-5216 in the rhesus monkey brain. [11C]AC-5216 entered the brain and remained at almost the same level in all measured brain regions during the scan time of 90 min. The uptake of [11C]AC-5216 was markedly decreased by pretreatment with AC-5216 and PK11195, despite initial increases in uptake. The uptake in the occipital cortex was reduced by AC-5216 at 1.0 mg/kg to ~30% of the control uptake, suggesting specific binding in vivo in the monkey brain. The percentage of reduction in [11C]AC-5216 uptake obtained with AC-5216 at 1.0 mg/kg was similar to that obtained with PK11195 at 5.0 mg/kg. This result confirmed that the binding site for AC-5216 in the PBR domain might be close to that for PK11195, consistent with the in vitro pharmacological result.

Human Studies


No publication is currently available.


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This MICAD chapter is not included in the Open Access Subset, because it was authored / co-authored by one or more investigators who was not a member of the MICAD staff.


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