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Molecular Imaging and Contrast Agent Database (MICAD) [Internet]. Bethesda (MD): National Center for Biotechnology Information (US); 2004-2013.

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Molecular Imaging and Contrast Agent Database (MICAD) [Internet].

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N-(2-[11C],5-Dimethoxybenzyl)-N-(5-fluoro-2-phenoxyphenyl)acetamide

[11C]DAA1106
, PhD
National Center for Biotechnology Information, NLM, NIH, Bethesda, MD, vog.hin.mln.ibcn@dacim

Created: ; Last Update: January 2, 2008.

Chemical name:N-(2-[11C],5-Dimethoxybenzyl)-N-(5-fluoro-2-phenoxyphenyl)acetamideimage 8139986 in the ncbi pubchem database
Abbreviated name:[11C]DAA1106
Synonym:
Agent Category:Compound
Target:Peripheral-type benzodiazepine receptor
Target Category:Receptor binding
Method of detection:PET
Source of signal/contrast:11C
Activation:No
Studies:
  • Checkbox In vitro
  • Checkbox Rodents
  • Checkbox Other non-primate mammals
  • Checkbox Non-human primates
  • Checkbox Humans
Click on the above structure for additional information in PubChem.

Background

[PubMed]

Benzodiazepines, such as diazepam, are potent psychoactive drugs used for their sedative and anxiolytic properties (1, 2). There are two types of benzodiazepine receptors, which have been identified as the central benzodiazepine receptor (CBR) and the peripheral benzodiazepine receptor (PBR). CBR is found exclusively in the central nervous system on the membranes of neurons and is coupled to the γ-aminobutyric acid receptor/chloride channel (3). In contrast, PBR is a mitochondrial protein found in brain and peripheral tissues (adrenal gland, heart, lung, kidney, and testis) (4). The brain has lower levels of PBR than do the peripheral tissues. Both glial cells and macrophages contain high levels of PBR (5-7). Increased PBR expression after brain injury or neuroinflammation is associated with microglial activation, such as occurs with the neuronal damage that accompanies several neurodegenerative diseases, including Alzheimer’s disease, Wernicke’s encephalopathy, multiple sclerosis, and epilepsy.

PBR has been studied in vivo with positron emission tomography (PET) using [11C]PK11195, an isoquinoline carboxamide with specific PBR-antagonistic activity. [11C]PK11195 is being developed as a PET agent for non-invasive study of microglia and macrophage activation in the brain, lung, and heart. However, accumulation of this tracer in the brain is limited. N-(2,5-Dimethoxybenzyl)-N-(5-fluoro-2-phenoxyphenyl)acetamide (DAA1106) was found to be a selective agonist for studying PBR in the central nervous system (8, 9). DAA1106 was reported to have a higher affinity for PBR in mitochondrial fractions of rat and monkey brains than did PK11195 (8, 9). Therefore, both tracers are able to cross the normal cell membrane to reach the mitochondrial receptor. [11C]DAA1106 is being developed as a PET agent for the non-invasive study of microglia and macrophage activation in the brain.

Synthesis

[PubMed]

In the report by Zhang et al. (10), [11C]DAA1106 was synthesized by alkylation of the desmethyl precursor (N-(5-fluoro-2-phenoxyphenyl)-N-(2-hydroxy-5-methoxybenzyl)-acetamide) with 11C-labeled methyl iodide in the presence of NaH. Subsequent high-performance liquid chromatography (HPLC) separation gave a radiochemical purity >98% with a total synthesis time of 22 min. The specific activity was 90–156 GBq/μmol (2.5–4.3 Ci/μmol) at end of synthesis (EOS). A reproducible radiochemical yield of 72% (decay-corrected) was reported.

Probst et al. (11) automated the synthesis of [11C]DAA1106 using a GE gas-phase synthesis module with high radioactivities of 11C-labeled methyl iodide. Radiochemical purities of 99% and specific activities of 100–200 GBq/μmol (2.7–5.4 Ci/μmol) were obtained at EOS. The methylation was performed in the presence of NaOH. The total synthesis time was 34 min from end of bombardment to EOS with radiochemical yields of 71–89% at EOS.

In Vitro Studies: Testing in Cells and Tissues

[PubMed]

In vitro binding studies of [3H]DAA1106 produced dissociation constant (Kd) values of 0.12 ± 0.03 and 0.43 ± 0.04 nM for mitochondrial fractions of rat and monkey cerebral cortex, respectively (9). The PBR maximal binding (Bmax) values were 161.03 ± 5.8 and 701 ± 70 fmol/mg protein for mitochondrial fractions of rat and monkey cerebral cortex, respectively. Regional distribution of [3H]DAA1106 in mitochondrial fractions of the rat brain revealed that the olfactory bulb has the highest Bmax (>400 fmol/mg protein), followed by the cerebellum, cerebral cortex, hypothalamus, striatum, hippocampus, and thalamus. This pattern of DAA1106 binding in the brain was later confirmed in rats by in vitro autoradiographic studies using [11C]DAA1106 (12).

Venneti et al. (13, 14) showed that [3H]DAA1106 exhibited ~5-fold lower Kd values compared with [3H](R)-PK11195 in normal rat brain tissue, whereas Bmax values were uniformly lower with [3H]DAA1106 compared with [3H](R)-PK11195. The relative contributions of astrocytes and microglia to [3H]DAA1106 bindings as PBR were assessed by combined immunostaining for astrocytes and activated microglia (CD68) with [3H]DAA1106 autoradiography on frozen brain sections obtained from rats with traumatic brain injury. [3H]DAA1106 binding co-registered with activated microglia more than astrocytes in the region of the contusion. Minimal [3H]DAA1106 binding as well as CD68 staining was observed in cortical regions in the contralateral hemisphere. [3H]DAA1106 binding was confirmed to be specific because it was displaced by unlabeled DAA1106 (1 ìM) in adjacent sections in the region of the contusion.

Animal Studies

Rodents

[PubMed]

Biodistribution studies in normal mice showed high accumulation of radioactivity in the lung (70.8% of injected dose (ID)/g), followed by the heart (16.5% ID/g), kidney (10.0% ID/g), adrenal gland (6.6% ID/g), and brain (3.5% ID/g) at 15 min after injection of [11C]DAA1106 (10). Radioactivity of the tracer was low in the liver and blood (2% ID/g). The regional distribution in the mouse brain showed rapid accumulation into all brain regions at 1 min after injection. The highest uptake was in the olfactory bulb (4.2% ID/g), followed by the cerebellum (3.5% ID/g), cerebral cortex (2.3% ID/g), striatum (1.8% ID/g), hippocampus (1.7% ID/g), hypothalamus (1.4% ID/g), and thalamus (1.2% ID/g) at 30 min after injection. Coadiministration of unlabeled DAA1106 decreased the accumulation in all brain regions, with the most significant reduction in the olfactory bulb and cerebellum. Almost all of the radioactivity in the brain was intact [11C]DAA1106 at 60 min after injection. The fraction of unchanged [11C]DAA1106 in blood samples, as determined by HPLC, was 65% at 5 min, 17% at 30 min, and 6% at 60 min. The major metabolite was found to be the debenzylated compound N-(5-fluoro-2-phenoxyphenyl)acetamide, which showed no binding to PBR or CBR (8). In later experiments, Venneti et al. (13) used PET imaging to find that [11C]DAA1106 was effectively displaced by DAA1106 in the lung (92%), heart (80%), and brain (75%).

Maeda et al. (12) reported ex vivo autoradiographic studies of [11C]DAA1106 brain binding in normal rats and in rats with focal hippocampus lesions induced by kainic acid. [11C]DAA1106 binding was highest in the olfactory bulb, followed by the cerebellum, pons/medulla, frontal cortex, and hippocampus at 30 min after injection. [11C]DAA1106 binding was increased in the focal hippocampal lesions by 1-fold (P < 0.05) over the control hippocampus, indicating an increase in PBR binding sites associated with microglia infiltration.

Venneti et al. (13) reported that LPS-lesioned rats exhibited increased brain accumulation of [11C]DAA1106 compared with [11C](R)-PK11195 as imaged by PET. [11C](R)-PK11195 accumulation was effectively blocked by either PK11195 or DAA1106, whereas [11C]DAA1106 was effectively blocked by DAA1106 and to a lesser extent by PK11195. [11C]DAA1106 showed greater retention than [11C](R)-PK11195 at the site of the contusion in rats with traumatic brain injury as assessed by ex vivo autoradiography (14).

Other Non-Primate Mammals

[PubMed]

[11C]DAA1106 PET imaging was performed in the abdomen of rabbits (n = 3) with accumulation in the kidney cortex at 60–75 min after injection (11). Injection of DAA1106 at 30 min after [11C]DAA1106 injection clearly displaced the radioactivity in the kidney cortex, indicating specific binding. The presence of PBR expression in the kidney cortex was confirmed by immunohistochemistry.

Non-Human Primates

[PubMed]

Using PET, Maeda et al. (12) obtained serial brain scans in one baboon after injections of 90.6 ± 9.3 MBq (2.4 ± 0.3 mCi) of [11C]DAA1106. Accumulation of radioactivity in the brain (occipital cortex, frontal cortex, and cerebellum) was rapid and remained at almost the same level during the 90-min scan. The radioactivity in the occipital cortex was only slightly higher than that in the frontal cortex and cerebellum. Co-injection and posttreatment injection (30 min after injection of the tracer) of DAA1106 (1 mg/kg) or PK11195 (5 mg/kg) enhanced inhibition and displacement of [11C]DAA1106 binding by 80% and 70%, respectively. These results confirmed that these changes represented alterations in specific binding. [11C]DAA1106 binding (0.02% dose/ml) was three-fold higher than [11C]PK11195 binding (0.005% dose/ml) in the monkey occipital cortex at 30 min after injection partly because of better lipophilicity and higher affinity of [11C]DAA1106. The log P values for [11C]PK11195 and [11C]DAA1106 were 2.7 and 3.7, respectively. DAA1106 was reported to have a two- to three-fold higher affinity for PBR in mitochondrial fractions of rat and monkey brains than did PK11195 (8, 9).

Human Studies

[PubMed]

Ikoma et al. (15) performed human PET studies using graphical analysis (GA), nonlinear least-squares (NLS) method, and multilinear analysis (MA) to evaluate the cerebral kinetics of [11C]DAA1106 in seven healthy subjects. Binding potential (BP) was calculated by NLS, and distribution volume (DV) was estimated by NLS, GA, and MA in various brain regions with use of a two-tissue compartmental model. DVs estimated with each method were well correlated. BP values were most reliably estimated by NLS. The highest BP value was in the thalamus (5.54), followed by the cerebellum (5.00), anterior cingulated (4.93), lateral temporal cortex (4.91), frontal cortex (4.86), parietal cortex (4.75), occipital cortex (4.70), and striatum (4.38).

NIH Support

RO1 MH64921, K24 MH01717, K08 HD40833

References

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Chaki S., Funakoshi T., Yoshikawa R., Okuyama S., Okubo T., Nakazato A., Nagamine M., Tomisawa K. Binding characteristics of [3H]DAA1106, a novel and selective ligand for peripheral benzodiazepine receptors. Eur J Pharmacol. 1999;371(2-3):197–204. [PubMed: 10357257]
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Zhang M.R., Kida T., Noguchi J., Furutsuka K., Maeda J., Suhara T., Suzuki K. [(11)C]DAA1106: radiosynthesis and in vivo binding to peripheral benzodiazepine receptors in mouse brain. Nucl Med Biol. 2003;30(5):513–9. [PubMed: 12831989]
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Probst K.C., Izquierdo D., Bird J.L., Brichard L., Franck D., Davies J.R., Fryer T.D., Richards H.K., Clark J.C., Davenport A.P., Weissberg P.L., Warburton E.A. Strategy for improved [(11)C]DAA1106 radiosynthesis and in vivo peripheral benzodiazepine receptor imaging using microPET, evaluation of [(11)C]DAA1106. Nucl Med Biol. 2007;34(4):439–46. [PubMed: 17499734]
12.
Maeda J., Suhara T., Zhang M.R., Okauchi T., Yasuno F., Ikoma Y., Inaji M., Nagai Y., Takano A., Obayashi S., Suzuki K. Novel peripheral benzodiazepine receptor ligand [11C]DAA1106 for PET: an imaging tool for glial cells in the brain. Synapse. 2004;52(4):283–91. [PubMed: 15103694]
13.
Venneti S., Lopresti B.J., Wang G., Slagel S.L., Mason N.S., Mathis C.A., Fischer M.L., Larsen N.J., Mortimer A.D., Hastings T.G., Smith A.D., Zigmond M.J., Suhara T., Higuchi M., Wiley C.A. A comparison of the high-affinity peripheral benzodiazepine receptor ligands DAA1106 and (R)-PK11195 in rat models of neuroinflammation: implications for PET imaging of microglial activation. J Neurochem. 2007;102(6):2118–31. [PubMed: 17555551]
14.
Venneti S., Wagner A.K., Wang G., Slagel S.L., Chen X., Lopresti B.J., Mathis C.A., Wiley C.A. The high affinity peripheral benzodiazepine receptor ligand DAA1106 binds specifically to microglia in a rat model of traumatic brain injury: implications for PET imaging. Exp Neurol. 2007;207(1):118–27. [PMC free article: PMC2042945] [PubMed: 17658516]
15.
Ikoma Y., Yasuno F., Ito H., Suhara T., Ota M., Toyama H., Fujimura Y., Takano A., Maeda J., Zhang M.R., Nakao R., Suzuki K. Quantitative analysis for estimating binding potential of the peripheral benzodiazepine receptor with [(11)C]DAA1106. J Cereb Blood Flow Metab. 2007;27(1):173–84. [PubMed: 16685259]

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