Molecular Imaging of Neurovascular Cell Death in Experimental Cerebral Stroke by PET
Ayelet Reshef 1*,
Anat Shirvan 1,
Rikki N. Waterhouse 2,
Hagit Grimberg 1,
Galit Levin 1,
Avi Cohen 1,
Luckner G. Ulysse 3,
Gad Friedman 1,
Gunnar Antoni 4,
and
Ilan Ziv 1
1 NST NeuroSurvival Technologies Ltd., Petach Tikva, Israel
2 Neurobiology and Imaging Program, Department of Biological Psychiatry, New York State Psychiatric Institute and Columbia University, New York, New York
3 Albany Molecular Research, Albany, New York
4 Imanet, Uppsala, Sweden
* To whom correspondence should be addressed. E-mail: ayelet{at}nst.co.il.
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Abstract |
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Clinical molecular imaging of apoptosis is a highly desirable yet unmet challenge. Here we provide the first report on 18F-labeled 5-fluoropentyl-2-methyl-malonic acid (18F-ML-10), a small-molecule, 18F-labeled PET tracer for the imaging of apoptosis in vivo; this report includes descriptions of the synthesis, radiolabeling, and biodistribution of this novel apoptosis marker. We also describe the use of 18F-ML-10 for small-animal PET of neurovascular cell death in experimental cerebral stroke in mice. Methods: 18F-ML-10 was synthesized by nucleophilic substitution from the respective mesylate precursor, and its biodistribution was assessed in healthy rats. Permanent occlusion of the middle cerebral artery (MCA) was induced in mice, and small-animal PET was performed 24 h later. Results: Efficient radiolabeling of ML-10 with 18F was achieved. Biodistribution studies with 18F-ML-10 revealed rapid clearance from blood (half-life of 23 min), a lack of binding to healthy tissues, and rapid elimination through the kidneys. No significant tracer metabolism in vivo was observed. Clear images of distinct regions of increased uptake, selectively in the ischemic MCA territory, were obtained in the in vivo small-animal PET studies. Uptake measurements ex vivo revealed 2-fold-higher uptake in the affected hemisphere and 6- to 10-fold-higher uptake in the region of interest of the infarct. The cerebral uptake of 18F-ML-10 was well correlated with histologic evidence of cell death. The tracer was retained in the stroke area but was cleared from blood and from intact brain areas. Conclusion: 18F-ML-10 is useful for noninvasive PET of neurovascular histopathology in ischemic cerebral stroke in vivo. Such an assessment may assist in characterization of the extent of stroke-related cerebral damage and in the monitoring of disease course and effect of treatment.
Key Words:
PET imaging, experimental stroke, apoptosis, middle cerebral artery occlusion
