TY - JOUR
T1 - Contribution of neuroinflammation to changes in [11C]flumazenil binding in the rat brain
T2 - Evaluation of the inflamed pons as reference tissue
AU - Parente, Andrea
AU - Vállez García, David
AU - Shoji, Alexandre
AU - Lopes Alves, Isadora
AU - Maas, Bram
AU - Zijlma, Rolf
AU - Dierckx, Rudi AJO
AU - Buchpiguel, Carlos A.
AU - de Vries, Erik FJ
AU - Doorduin, Janine
N1 - Publisher Copyright:
© 2017 Elsevier Inc.
PY - 2017/6/1
Y1 - 2017/6/1
N2 - Introduction [11C]Flumazenil is a well–known PET tracer for GABAA receptors and is mainly used as an imaging biomarker for neuronal loss. Recently, GABAA receptors on immune cells have been investigated as target for modulation of inflammation. Since neuronal loss is often accompanied by neuroinflammation, PET imaging with [11C]flumazenil is potentially affected by infiltrating immune cells. This may also compromise the validity of using the pons as reference tissue in quantitative pharmacokinetic analysis. This study aims to evaluate whether inflammatory processes in the brain can influence [11C]flumazenil uptake and affect the outcome of pharmacokinetic modeling when the pons is used as reference tissue. Methods The herpes simplex encephalitis (HSE) rat model is known to cause neuroinflammation in the brainstem. Dynamic [11C]flumazenil PET scans of 60-min, accompanied by arterial blood sampling and metabolite analysis, were acquired at day 6–7 days post-infection of male Wistar rats (HSE, n = 5 and control, n = 6). Additionally, the GABAA receptor was saturated by injection of unlabeled flumazenil prior to the tracer injection in 4 rats per group. PET data were analyzed by pharmacokinetic modeling. Results No statistically significant differences were found in the volume of distribution (VT) or non-displaceable binding potential (BPND) between control and HSE rats in any of the brain regions. Pre-saturation with unlabeled flumazenil resulted in a statistically significant reduction in [11C]flumazenil VT in all brain regions. The BPND obtained from SRTM exhibited a good correlation to DVR – 1 values from the two-tissue compartment model, coupled with some level of underestimation. Conclusion Reliable quantification of [11C]flumazenil binding in rats can be obtained by pharmacokinetic analysis using the pons as a pseudo-reference tissue even in the presence of strong acute neuroinflammation.
AB - Introduction [11C]Flumazenil is a well–known PET tracer for GABAA receptors and is mainly used as an imaging biomarker for neuronal loss. Recently, GABAA receptors on immune cells have been investigated as target for modulation of inflammation. Since neuronal loss is often accompanied by neuroinflammation, PET imaging with [11C]flumazenil is potentially affected by infiltrating immune cells. This may also compromise the validity of using the pons as reference tissue in quantitative pharmacokinetic analysis. This study aims to evaluate whether inflammatory processes in the brain can influence [11C]flumazenil uptake and affect the outcome of pharmacokinetic modeling when the pons is used as reference tissue. Methods The herpes simplex encephalitis (HSE) rat model is known to cause neuroinflammation in the brainstem. Dynamic [11C]flumazenil PET scans of 60-min, accompanied by arterial blood sampling and metabolite analysis, were acquired at day 6–7 days post-infection of male Wistar rats (HSE, n = 5 and control, n = 6). Additionally, the GABAA receptor was saturated by injection of unlabeled flumazenil prior to the tracer injection in 4 rats per group. PET data were analyzed by pharmacokinetic modeling. Results No statistically significant differences were found in the volume of distribution (VT) or non-displaceable binding potential (BPND) between control and HSE rats in any of the brain regions. Pre-saturation with unlabeled flumazenil resulted in a statistically significant reduction in [11C]flumazenil VT in all brain regions. The BPND obtained from SRTM exhibited a good correlation to DVR – 1 values from the two-tissue compartment model, coupled with some level of underestimation. Conclusion Reliable quantification of [11C]flumazenil binding in rats can be obtained by pharmacokinetic analysis using the pons as a pseudo-reference tissue even in the presence of strong acute neuroinflammation.
KW - GABA
KW - Herpes simplex encephalitis
KW - Neuroinflammation
KW - PET
KW - Pharmacokinetic modeling
KW - [C]flumazenil
UR - http://www.scopus.com/inward/record.url?scp=85016417802&partnerID=8YFLogxK
U2 - 10.1016/j.nucmedbio.2017.03.001
DO - 10.1016/j.nucmedbio.2017.03.001
M3 - Article
C2 - 28364664
AN - SCOPUS:85016417802
SN - 0969-8051
VL - 49
SP - 50
EP - 56
JO - Nuclear Medicine and Biology
JF - Nuclear Medicine and Biology
ER -