Abstract
Impairment of the metabotropic glutamate receptor 5 (mGluR5) has been implicated with various neurologic disorders. Although mGluR5 density can be quantified with the PET radiotracer [11C]ABP688, the methods for reproducible quantification of [11C]ABP688 PET imaging in mice have not been thoroughly investigated yet. Thus, this study aimed to assess and validate cerebellum as reference region for simplified reference tissue model (SRTM), investigate the feasibility of a noninvasive cardiac image-derived input function (IDIF) for relative quantification, to validate the use of a PET template instead of an MRI template for spatial normalization, and to determine the reproducibility and within-subject variability of [11C]ABP688 PET imaging in mice. Blocking with the mGluR5 antagonist MPEP resulted in a reduction of [11C]ABP688 binding of 41% in striatum (p < 0.0001), while no significant effect could be found in cerebellum (−4.8%, p > 0.99) indicating cerebellum as suitable reference region for mice. DVR-1 calculated using a noninvasive IDIF and an arteriovenous input function correlated significantly when considering the cerebellum as the reference region (striatum: DVR-1, r = 0.978, p < 0.0001). Additionally, strong correlations between binding potential calculated from SRTM (BPND) with DVR-1 based on IDIF (striatum: r = 0.980, p < 0.0001) and AV shunt (striatum: r = 0.987, p < 0.0001). BPND displayed higher discrimination power than VT values in determining differences between wild-types and heterozygous Q175 mice, an animal model of Huntington's disease. Furthermore, we showed high agreement between PET- and MRI-based spatial normalization approaches (striatum: r = 0.989, p < 0.0001). Finally, both spatial normalization approaches did not reveal any significant bias between test-retest scans, with a relative difference below 5%. This study indicates that noninvasive quantification of [11C]ABP688 PET imaging is reproducible and cerebellum can be used as reference region in mice.
Highlights
Glutamate is the most prominent neurotransmitter in the brain
To evaluate a noninvasive approach for quantification of [11C]ABP688, arterial input function (IPF) based on AV shunt and image-derived input function (IDIF) were compared
When considering the cerebellum as reference region, correlations between distribution volume ratio-1 (DVR-1) based on AV shunt and IDIF were strong and highly significant in all regions (r = 0.978, p < 0.0001 in striatum; r = 0.967, p < 0.0001 in cortex; r = 0.955, p < 0.0001 in hippocampus; r = 0.934, p < 0.0001 in thalamus) (Figure 2B and Supplementary Table 2)
Summary
Glutamate is the most prominent neurotransmitter in the brain. The metabotropic glutamate receptors (mGluRs) are G-protein coupled receptors which modulate synaptic transmission and neuronal excitability [1]. Impairment of the mGluR Group I (mGluR1 and mGluR5) has been implicated with various neurologic disorders, including Huntington’s disease (HD) [2]. HD is an autosomal dominant neurodegenerative disorder [3] caused by an expanded CAG repeat in exon 1 of the gene encoding the protein huntingtin (HTT) [4]. MGluR5 is hypothesized to play an important role in the pathogenesis of HD [2, 7] and it represents an interesting target to image in vivo by means of positron emission tomography (PET). [11C]ABP688 PET imaging has successfully been used to quantify mGluR5 at preclinical and clinical level [8,9,10,11], the methods for reproducible quantification of [11C]ABP688 PET imaging in mice have not been thoroughly investigated yet
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
