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.

[18F]-BMS-747158-02PET imaging for evaluating hepatic mitochondrial complex 1dysfunction in a mouse model of non-alcoholic fatty liver disease

“…18 F-BMS is selectively taken up into the heart because of the high density of mitochondria in the cardiac muscle. There are some reports that uptake of MC-1 probes, including 18 F-BMS, was inhibited by pre-injection of rotenone, a MC-1 inhibitor not only in the heart but also in the brain [ 21 , 22 ]. In the present study, hepatic uptake of 18 F-BMS was also reduced by pre-injection of rotenone, indicating that 18 F-BMS is bound to MC-1 in the liver.…”

Non-invasive evaluation of neuroprotective drug candidates for cerebral infarction by PET imaging of mitochondrial complex-I activity

“…In the present study, we prepared a PET probe specific for MC-I activity to visualize the ischemic brain damage from the acute through subacute phase, and to evaluate the therapeutic effect of FK506-liposomes on cerebral I/R injury. It has been reported that unexpectedly high [ 18 F]FDG uptake and apparent intense staining with TTC are observable in the damaged region at the subacute phase after cerebral I/R in spite of the neurodegenerative death in the area 16 . This phenomenon results from the exclusive production of ATP by activated inflammatory cells such as microglia and macrophages via enhanced glycolysis, the metabolic pathway with a low contribution of the electron transport chain for ATP production 17 18 .…”

TSPO imaging in stroke: from animal models to human subjects

“…Whether the increased metabolism in the periinfarct zone was purely due to increased metabolic demand from neurons or a combination of neuronal activity and glial proliferation remains unclear, however together with the presence of neuroinflammation it is likely to indicate an increased risk to secondary inflammatory damage for the brain tissue in this area. Fukumoto et al [45,46] further investigated, in two multi-tracer studies, using [ 11 C]-(R)-PK11195 and [ 11 C]flumazenil for central benzodiazepine receptor (CBR) and [ 18 F]FDG for glucose metabolism [45] or [ 18 F]BMS-747158-02 (Mitochondrial Complex-1 ligand) [46], the time-course and localisation of TSPO expression after permanent stroke (photothrombotic model). These authors found that [ 11 C]-(R)-PK11195 uptake matched in localisation the hypermetabolism detected in the periinfarcted area by [ 18 F]FDG, whereas a decrease in [ 18 F]flumazenil [45] and [ 18 F]BMS-747158-02 [46] uptake could be detected in the infarct core.…”

“…Fukumoto et al [45,46] further investigated, in two multi-tracer studies, using [ 11 C]-(R)-PK11195 and [ 11 C]flumazenil for central benzodiazepine receptor (CBR) and [ 18 F]FDG for glucose metabolism [45] or [ 18 F]BMS-747158-02 (Mitochondrial Complex-1 ligand) [46], the time-course and localisation of TSPO expression after permanent stroke (photothrombotic model). These authors found that [ 11 C]-(R)-PK11195 uptake matched in localisation the hypermetabolism detected in the periinfarcted area by [ 18 F]FDG, whereas a decrease in [ 18 F]flumazenil [45] and [ 18 F]BMS-747158-02 [46] uptake could be detected in the infarct core. In term of time-course, they showed that TSPO expression was low 1 day post-stroke [46] and increases progressively to peak around day 7 post-ischemia and decrease thereafter (day 14) [45].…”