TY - JOUR
T1 - Detecting Validated Intracellular ROS Generation with 18F-dihydroethidine-Based PET
AU - Waters, Edward C T
AU - Baark, Friedrich
AU - Yu, Zilin
AU - Mota, Filipa
AU - Eykyn, Thomas R
AU - Yan, Ran
AU - Southworth, Richard
N1 - Funding Information:
EW would like to thank the Engineering and Physical Sciences Research Council (EPSRC) PhD studentship [EP/M506357/1] for supporting this work. This work was also supported by British Heart Foundation (BHF) project grant [PG/16/43/32141], BHF project grant [PG/15/60/31629], EPSRC Programme Grant [EP/S032789/1, “MITHRAS”], and EPSRC Programme Grant [EP/S019901/1, “RedOX”].
Publisher Copyright:
© 2021, Crown.
PY - 2021/11/24
Y1 - 2021/11/24
N2 - Purpose: To determine the sensitivity of the
18F-radiolabelled dihydroethidine analogue ([
18F]DHE) to ROS in a validated ex vivo model of tissue oxidative stress. Procedures: The sensitivity of [
18F]DHE to various ROS-generating systems was first established in vitro. Then, isolated rat hearts were perfused under constant flow, with contractile function monitored by intraventricular balloon. Cardiac uptake of infused [
18F]DHE (50–150 kBq.min
−1) was monitored by γ-detection, while ROS generation was invoked by menadione infusion (0, 10, or 50 μm), validated by parallel measures of cardiac oxidative stress. Results: [
18F]DHE was most sensitive to oxidation by superoxide and hydroxyl radicals. Normalised [
18F]DHE uptake was significantly greater in menadione-treated hearts (1.44 ± 0.27) versus control (0.81 ± 0.07) (p < 0.05, n = 4/group), associated with concomitant cardiac contractile dysfunction, glutathione depletion, and PKG1α dimerisation. Conclusion: [
18F]DHE reports on ROS in a validated model of oxidative stress where perfusion (and tracer delivery) is unlikely to impact its pharmacokinetics.
AB - Purpose: To determine the sensitivity of the
18F-radiolabelled dihydroethidine analogue ([
18F]DHE) to ROS in a validated ex vivo model of tissue oxidative stress. Procedures: The sensitivity of [
18F]DHE to various ROS-generating systems was first established in vitro. Then, isolated rat hearts were perfused under constant flow, with contractile function monitored by intraventricular balloon. Cardiac uptake of infused [
18F]DHE (50–150 kBq.min
−1) was monitored by γ-detection, while ROS generation was invoked by menadione infusion (0, 10, or 50 μm), validated by parallel measures of cardiac oxidative stress. Results: [
18F]DHE was most sensitive to oxidation by superoxide and hydroxyl radicals. Normalised [
18F]DHE uptake was significantly greater in menadione-treated hearts (1.44 ± 0.27) versus control (0.81 ± 0.07) (p < 0.05, n = 4/group), associated with concomitant cardiac contractile dysfunction, glutathione depletion, and PKG1α dimerisation. Conclusion: [
18F]DHE reports on ROS in a validated model of oxidative stress where perfusion (and tracer delivery) is unlikely to impact its pharmacokinetics.
UR - http://www.scopus.com/inward/record.url?scp=85120884941&partnerID=8YFLogxK
U2 - 10.1007/s11307-021-01683-0
DO - 10.1007/s11307-021-01683-0
M3 - Article
C2 - 34820762
SN - 1536-1632
JO - Molecular Imaging and Biology
JF - Molecular Imaging and Biology
ER -