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.
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.
Central Research Laboratory, Hamamatsu Photonics K.K., Hamamatsu, Shizuoka, Japan.
Dai
D
Fukumoto
Shingo
S
Nishiyama
Norihiro
N
Harada
Shigeyuki
S
Yamamoto
Hideo
H
Tsukada
D000577:Amides; D000818:Animals; D002545:Brain Ischemia / Q000000981:diagnostic imaging*; D042967:Electron Transport Complex I / Q000032:analysis* / Q000037:antagonists & inhibitors; D005462:Fluorine Radioisotopes; D007546:Isoquinolines; D008024:Ligands; D008297:Male; D009457:Neuroglia / Q000737:chemistry / Q000473:pathology; D009474:Neurons / Q000737:chemistry / Q000000981:diagnostic imaging* / Q000473:pathology; D049268:Positron-Emission Tomography; D011724:Pyridazines; D051381:Rats; D017207:Rats, Sprague-Dawley; D011963:Receptors, GABA-A / Q000032:analysis; D012402:Rotenone / Q000494:pharmacology; D013778:Tetrazolium Salts / Q000494:pharmacology
C504060:(R)-(11C)1-(2-chlorophenyl)-N-methyl-N-(1-methylpropyl)-3-isoquinolinecarboxamide; D000577:Amides; C525920:BMS 747158-02; D005462:Fluorine Radioisotopes; D007546:Isoquinolines; D008024:Ligands; D011724:Pyridazines; D011963:Receptors, GABA-A; D013778:Tetrazolium Salts; D012402:Rotenone; C009591:triphenyltetrazolium; D042967:Electron Transport Complex I