Assessment of myocardial inflammation produced by experimental coronary occlusion and reperfusion with 99mTc-RP517, a new leukotriene B4 receptor antagonist that preferentially labels neutrophils in vivo.
BACKGROUND
99mTc-RP517 is a new leukotriene B4 (LTB4) receptor antagonist developed for imaging acute inflammation or infection. A unique property of 99mTc-RP517 is its ability to label white blood cells in vivo after intravenous injection. The goals of this study were to determine relative 99mTc-RP517 binding to human leukocyte subtypes and the 99mTc-RP517 uptake pattern in canine myocardium where inflammation was induced by either coronary occlusion and reperfusion or tumor necrosis factor alpha (TNFalpha) injection.


RESULTS
Fluorescence-activated cell sorter analysis was performed on whole human blood (n=2) and isolated neutrophils (n= 4) with a fluorescent analog of 99mTc-RP517, [F]-RP517. In whole blood, [F]-RP517 (500 nmol/L) preferentially labeled neutrophils. On isolated neutrophils, [F]-RP517 (10 nmol/L) binding was inhibited by 44% when LTB4 (400 nmol/L) was added. 99mTc-RP517 was injected intravenously in anesthetized, open-chest dogs before coronary occlusion (90 minutes) and reperfusion (120 minutes) (n=9) or before intramyocardial TNFalpha injection (n=3). Ex vivo images of heart slices were acquired. The left ventricle was divided into 72 segments for flow and 99mTc-RP517 uptake analysis. There was an inverse exponential relationship between 99mTc-RP517 uptake and occlusion flow (r=0.73). In the same 15 segments, 99mTc-RP517 uptake was highly correlated with the neutrophil enzyme myeloperoxidase (r=0.91). Ex vivo images revealed tracer uptake in the reperfused area (ischemic to normal count ratio=2.7+/-0.2).


CONCLUSIONS
RP517 binds to the neutrophil LTB4 receptor after intravenous injection. After reperfusion, 99mTc-RP517 uptake correlated with myeloperoxidase and was observed on ex vivo images, indicating that this tracer may have potential as an inflammation-imaging agent.
Riou
Laurent M
LM
University of Virginia Health System, Charlottesville, Va 22908-0500, USA.
Ruiz
Mirta
M
Sullivan
Gail W
GW
Linden
Joel
J
Leong-Poi
Howard
H
Lindner
Jonathan R
JR
Harris
Thomas D
TD
Beller
George A
GA
Glover
David K
DK
D000818:Animals; D001345:Autoradiography; D001667:Binding, Competitive; D003326:Coronary Circulation; D003327:Coronary Disease / Q000503:physiopathology*; D004285:Dogs; D004333:Drug Administration Routes; D005434:Flow Cytometry; D006439:Hemodynamics; D006801:Humans; D007249:Inflammation / Q000139:chemically induced / Q000175:diagnosis*; D007267:Injections; D007275:Injections, Intravenous; D015425:Myocardial Reperfusion; D009205:Myocarditis / Q000139:chemically induced / Q000175:diagnosis*; D009206:Myocardium / Q000276:immunology / Q000378:metabolism; D009504:Neutrophils / Q000166:cytology / Q000276:immunology / Q000378:metabolism*; D015609:Organotechnetium Compounds / Q000008:administration & dosage / Q000493:pharmacokinetics; D009195:Peroxidase / Q000378:metabolism; D011237:Predictive Value of Tests; D018102:Receptors, Leukotriene B4 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D015427:Reperfusion Injury / Q000503:physiopathology; D014409:Tumor Necrosis Factor-alpha / Q000008:administration & dosage / Q000494:pharmacology
D015609:Organotechnetium Compounds; C425527:RP517; D018102:Receptors, Leukotriene B4; D014409:Tumor Necrosis Factor-alpha; D009195:Peroxidase