18F-FEAnGA for PET of β-glucuronidase activity in neuroinflammation.
Activation of microglia is a hallmark of inflammatory, infectious, and degenerative diseases of the central nervous system. Several studies have indicated that there is an increase in release of β-glucuronidase by activated microglia into the extracellular space at the site of neuroinflammation. β-glucuronidase is involved in the hydrolysis of glycosaminoglycans on the cell surface and the degradation of the extracellular matrix. Therefore, β-glucuronidase might be a biomarker for ongoing neurodegeneration induced by neuroinflammation. In this study, we investigated whether the PET tracer (18)F-FEAnGA was able to detect β-glucuronidase release during neuroinflammation in a rat model of herpes encephalitis.


METHODS
Male Wistar rats were intranasally inoculated with herpes simplex virus 1 (HSV-1) or phosphate-buffered saline as a control. (11)C-(R)-PK11195 and (18)F-FEAnGA small-animal PET scans were acquired for 60 min. Logan graphical analysis was used to calculate (18)F-FEAnGA distribution volumes (DV(Logan)) in various brain areas.


RESULTS
After administration of (18)F-FEAnGA, the area under the activity concentration-versus-time curve of the whole brain was 2 times higher in HSV-1-infected rats than in control rats. In addition, the DV(Logan) of (18)F-FEAnGA was most increased in the frontopolar cortex, frontal cortex, bulbus olfactorius, cerebral cortex, cerebellum, and brainstem of HSV-1-infected rats, when compared with control rats. The conversion of (18)F-FEAnGA to 4-hydroxy-3-nitrobenzyl alcohol was found to be 1.6 times higher in HSV-1-infected rats than in control rats and correlated with the DV(Logan) of (18)F-FEAnGA in the same areas of the brain. Furthermore, the DV(Logan) of (18)F-FEAnGA also correlated with β-glucuronidase activity in the same brain regions. In addition, DV(Logan) of (18)F-FEAnGA showed a tendency to correlate with (11)C-(R)-PK11195 uptake (marker for activated microglia) in the same brain regions.


CONCLUSIONS
Despite relatively low brain uptake, (18)F-FEAnGA was able to detect an increased release of β-glucuronidase during neuroinflammation.
Department of Nuclear Medicine and Molecular Imaging, University Medical Center Groningen, Groningen, The Netherlands.
Inês F
IF
Antunes
Janine
J
Doorduin
Hidde J
HJ
Haisma
Philip H
PH
Elsinga
Aren
A
van Waarde
Antoon T M
AT
Willemsen
Rudi A
RA
Dierckx
Erik F J
EF
de Vries
D000818:Animals; D001592:Benzyl Alcohols / Q000378:metabolism; D001711:Biotransformation; D001921:Brain / Q000000981:diagnostic imaging; D020803:Encephalitis, Herpes Simplex / Q000000981:diagnostic imaging / Q000201:enzymology; D005965:Glucuronates / Q000138:chemical synthesis / Q000493:pharmacokinetics; D005966:Glucuronidase / Q000378:metabolism*; D018259:Herpesvirus 1, Human; D007091:Image Processing, Computer-Assisted; D007546:Isoquinolines; D007553:Isotope Labeling; D008297:Male; D009443:Neuritis / Q000000981:diagnostic imaging* / Q000201:enzymology*; D009578:Nitrobenzenes / Q000378:metabolism; D049268:Positron-Emission Tomography / Q000379:methods*; D019275:Radiopharmaceuticals / Q000138:chemical synthesis / Q000493:pharmacokinetics; D051381:Rats; D017208:Rats, Wistar; D014018:Tissue Distribution
C571523:1-O-(4-(2-fluoroethylcarbamoyloxymethyl)-2-nitrophenyl)-O-glucopyronuronate; D001592:Benzyl Alcohols; D005965:Glucuronates; D007546:Isoquinolines; D009578:Nitrobenzenes; D019275:Radiopharmaceuticals; C099263:2-hydroxy-5-nitrobenzyl alcohol; D005966:Glucuronidase; C037850:PK 11195