Myeloperoxidase activity imaging using (67)Ga labeled substrate.
OBJECTIVE
The aim of the study is to assess the feasibility of imaging specific activity of myeloperoxidase (MPO), a leukocyte enzyme with important roles in inflammation and atherosclerosis, by single photon emission computed tomography (SPECT) using a novel (67)Ga-labeled radiotracer obtained by conjugating desferrioxamine (DF) and hydroxyindolyl acetic acid in vivo.


METHODS
A reducing substrate of MPO (I) was synthesized by reacting commercially available DF with 2-(5-hydroxy-1H-indol-3-yl) acetic acid in the presence of a coupling agent [dicyclohexyl carbodiimide (DCC)]. The chelating unit was labeled with (67)Ga, and its interaction with MPO was characterized using MALDI-TOF and UV-vis. Mice with Matrigel implants containing human MPO were used to model diseased tissues rich in MPO. Three hours after the injection of (67)Ga-I, SPECT/computed tomography (CT) imaging was performed on a high-resolution Gamma Medica X-SPECT system. Biodistribution studies were performed six hours after the injection of the radiotracer.


RESULTS
The feasibility of compound I oligomerization in the presence of MPO and MPO-mediated cross-linking with proteins was initially confirmed in vitro. In vivo, a 2.7-fold increase in target-to-muscle ratio could be measured in MPO-containing Matrigel implants in mice. Biodistribution experiments demonstrated a 60% increase of radioactivity in MPO-containing vs. control (contralateral) Matrigel implants.


CONCLUSIONS
(67)Ga-I can be used to image MPO activity in a model system. The accumulation mechanism is based on a differential pharmacokinetics because of the size increase resulting from (67)Ga-I interaction with the target enzyme.
Querol Sans
Manel
M
Department of Radiology, University of Massachusetts Medical School, 55 Lake Ave North, Worcester, MA 01655, USA.
Chen
John W
JW
Weissleder
Ralph
R
Bogdanov
Alexei A
AA
D000818:Animals; D002851:Chromatography, High Pressure Liquid; D005710:Gallium Radioisotopes / Q000378:metabolism; D007700:Kinetics; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D015394:Molecular Structure; D009195:Peroxidase / Q000032:analysis / Q000378:metabolism*; D013057:Spectrum Analysis; D013379:Substrate Specificity; D014057:Tomography, X-Ray Computed
D005710:Gallium Radioisotopes; D009195:Peroxidase