Detection of ischemic neuronal damage with [¹⁸F]BMS-747158-02, a mitochondrial complex-1 positron emission tomography ligand: small animal PET study in rat brain.

Abstract

The acute and subacute ischemic neuronal damage in rat brain caused by photochemically induced thrombosis (PIT) was imaged using [¹⁸F]BMS-747158-02 ([¹⁸F]BMS) for mitochondrial complex-1 (MC-1) and [¹¹C](R)-PK11195 ([¹¹C](R)-PK) for peripheral benzodiazepine receptor [PBR; translocator protein] at preischemic "Normal," 1 (day 1), and 7 days (day 7) after ischemic insult. When [¹⁸F]BMS was intravenously injected into "Normal" rat, it was rapidly taken up into the brain, in which it showed a homogeneous distribution, and the uptake was suppressed by rotenone, a specific MC-1 inhibitor. The specificity of [¹⁸F]BMS binding to MC-1 was also confirmed by living brain slice imaging. At day 1, [¹⁸F]BMS uptake was low in infarct and peri-infarct regions where neuronal damage was detected by 2,3,5-triphenyltetrazolium chloride (TTC) staining. At day 7, the damaged areas determined using [¹⁸F]BMS revealed some discrepancy from those detected by TTC staining, suggesting that TTC stained not only surviving cells but also activated microglial cells in the peri-infarct region. This was also confirmed by [¹¹C](R)-PK imaging and immunohistochemical assessment with Iba1 antibody. In contrast, the uptake pattern of [¹⁸F]BMS was consistent with immunohistochemical assessment with NeuN antibody at both days 1 and 7. These results demonstrated that [¹⁸F]BMS could be a promising positron emission tomography ligand to assess the neuronal damage induced by ischemic insult in both acute and subacute phases.

• Authors: Dai Fukumoto, Shingo Nishiyama, Norihiro Harada, Shigeyuki Yamamoto, Hideo Tsukada
• Journal: Synapse (New York, N.Y.) (Synapse) Vol. 66 Issue 10 Pg. 909-17 (Oct 2012) ISSN: 1098-2396 [Electronic] United States
• PMID: 22807129 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2012 Wiley Periodicals, Inc.

Chemical References

• (R)-(11C)1-(2-chlorophenyl)-N-methyl-N-(1-methylpropyl)-3-isoquinolinecarboxamide
• Amides
• BMS 747158-02
• Fluorine Radioisotopes
• Isoquinolines
• Ligands
• Pyridazines
• Receptors, GABA-A
• Tetrazolium Salts
• Rotenone
• triphenyltetrazolium
• Electron Transport Complex I

Topics

• Amides
• Animals
• Brain Ischemia (diagnostic imaging)
• Electron Transport Complex I (analysis, antagonists & inhibitors)
• Fluorine Radioisotopes
• Isoquinolines
• Ligands
• Male
• Neuroglia (chemistry, pathology)
• Neurons (chemistry, diagnostic imaging, pathology)
• Positron-Emission Tomography
• Pyridazines
• Rats
• Rats, Sprague-Dawley
• Receptors, GABA-A (analysis)
• Rotenone (pharmacology)
• Tetrazolium Salts (pharmacology)