Noninvasive Relative Quantification of [11C]ABP688 PET Imaging in Mice Versus an Input Function Measured Over an Arteriovenous Shunt

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.

Validation and noninvasive kinetic modeling of [11C]UCB-J PET imaging in mice

“…39 Although this approach is not suitable for absolute quantification, since it often overestimates the blood activity, we previously validated it to be reliable for comparative studies. 28 Kinetic analysis of the TACs indicated a near perfect agreement between V T (IDIF) values estimated using either 1TCM or 2TCM (r ¼ 0.999). According to model selection criteria (AIC, MSC, and F-test), 1TCM was the preferred model, as also suggested by the more accurate K 1 estimations in agreement with the previously published human data.…”

In vitro and In vivo Assessment of Suitable Reference Region and Kinetic Modelling for the mGluR1 Radioligand [11C]ITDM in Mice

“…However, invasive arterial blood sampling in mice presents several challenges and limitations in the perspective of longitudinal studies due to the small amount of blood collectable and since it is an end of life procedure. Hence, an attractive approach to perform noninvasive quantification is the application of an IDIF [21] to bypass the need for an invasive input function as we previously validated in mice over an atereriovenous shunt for the mGluR5 radiotracer [ 11 C]ABP688 [11]. Similar to the findings for [ 11 C]ABP688 [11], the IDIF overestimated the tail of the [ 11 C]ITDM input function, thus resulted in lower V T values.…”

“…Two Siemens Inveon PET/CT scanners (Siemens Preclinical Solution, Knoxville, USA) were used to acquire the dynamic microPET/computed tomography (CT) images. Animal preparation was performed as previously described [11,12]. Details of the PET acquisition are provided in the ESM.…”

“…During the baseline and blocking study, regional TACs were fitted by the Logan plot method [14] using the noninvasive IDIF as previously validated [11]. This approach allows comparative studies to be performed in mice, avoiding blood sampling, which is invasive and not feasible for longitudinal studies.…”

“…Comparison of invasive and noninvasive input functions for [11 C]ITDM quantification. a Average plasma SUV timeactivity curves (TACs) corrected and uncorrected for radiometabolism and b correlation between V T (AV shunt) based on 2TCM using plasma input function corrected (AV shunt, Corr) and uncorrected for radiometabolism (AV shunt, Uncorr).…”