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

Abstract

Synaptic pathology is associated with several brain disorders, thus positron emission tomography (PET) imaging of synaptic vesicle glycoprotein 2A (SV2A) using the radioligand [¹¹C]UCB-J may provide a tool to measure synaptic alterations. Given the pivotal role of mouse models in understanding neuropsychiatric and neurodegenerative disorders, this study aims to validate and characterize [¹¹C]UCB-J in mice. We performed a blocking study to verify the specificity of the radiotracer to SV2A, examined kinetic models using an image-derived input function (IDIF) for quantification of the radiotracer, and investigated the in vivo metabolism. Regional TACs during baseline showed rapid uptake of [¹¹C]UCB-J into the brain. Pretreatment with levetiracetam confirmed target engagement in a dose-dependent manner. V_{T (IDIF)} values estimated with one- and two-tissue compartmental models (1TCM and 2TCM) were highly comparable (r=0.999, p < 0.0001), with 1TCM performing better than 2TCM for K_{1 (IDIF)}. A scan duration of 60 min was sufficient for reliable V_{T (IDIF)} and K_{1 (IDIF)} estimations. In vivo metabolism of [¹¹C]UCB-J was relatively rapid, with a parent fraction of 22.5 ± 4.2% at 15 min p.i. In conclusion, our findings show that [¹¹C]UCB-J selectively binds to SV2A with optimal kinetics in the mouse representing a promising tool to noninvasively quantify synaptic density in comparative or therapeutic studies in neuropsychiatric and neurodegenerative disorder models.

Keywords: Animal models; SV2A; kinetic modeling; positron emission tomography; synaptic density.

Figure 1.

Validation of [¹¹C]UCB-J binding in the mouse brain. (a) Effect of blockade with levetiracetam (LEV) on [¹¹C]UCB-J uptake in WT mice. Parametric microPET images are overlaid onto a MRI mouse brain template for anatomical localization. (b) SUV time-activity curves in four brain regions during baseline and pretreatment with levetiracetam for a 90-min acquisition. (c) V_{T (IDIF)} (Logan) quantification during blockade resulted in a statistically significant reduced values in all investigated regions compared to baseline. ****p < 0.0001. Baseline: n = 10; LEV: n = 4 per dose. STR: striatum; THAL: thalamus; MC: motor cortex; HC: hippocampus; V_{T (IDIF)}: total volume of distribution using IDIF.

Figure 2.

Comparison of the total volume of distribution (V_T) and K₁ values determined using 1TCM and 2TCM based on IDIF. Correlation of the V_{T (IDIF)} (a) and K_{1 (IDIF)} (b) values calculated using 1TCM and 2TCM based on 90-min acquisition. The solid line represents the linear regression, while the dashed line depicts the identity line. (c and d) Bland–Altman plot to compare 1TCM and 2TCM in estimation of V_{T (IDIF)} and K_{1 (IDIF)}, respectively. Dashed line represents the bias between the two approaches, while the dotted lines denote the 95% limits of agreement. n = 10. Each symbol represents a different region. 1TCM: one-tissue compartmental model; 2TCM: two-tissue compartmental model; V_{T (IDIF)}: total volume of distribution using IDIF.

Figure 3.

[¹¹C]UCB-J PET imaging in the mouse brain. (a) Average microPET parametric images for V_{T (IDIF)} and K_{1 (IDIF)} of [¹¹C]UCB-J in healthy WT mice using 1TCM over 90-min acquisition. Parametric microPET images are overlaid onto a MRI mouse brain template for anatomical localization. (b) Regional [¹¹C]UCB-J V_{T (IDIF)} values. (c) Regional [¹¹C]UCB-J K_{1 (IDIF)} values. n = 10. 1TCM: one-tissue compartmental model; V_{T (IDIF)} : total volume of distribution using IDIF; STR: striatum; TH: thalamus; MC: motor cortex; HC: hippocampus; CB: cerebellum.

Figure 4.

Time stability of the outcome parameters in different brain regions. V_{T (IDIF)} and K_{1 (IDIF)} calculated using 1TCM (a and b) and V_{T (IDIF)} based on Logan plot (c) normalized to the values obtained during 90-min acquisition. Correlations of the outcome parameters V_{T (IDIF)} and K_{1 (IDIF)} calculated using 1TCM (d and e) and V_{T (IDIF)} based on Logan plot (f) when shortening the acquisition time from 90 to 60 min. n = 10. 1TCM = one-tissue compartmental model, V_{T (IDIF)} = total volume of distribution using IDIF.

Figure 5.

Population-based plasma metabolism of [¹¹C]UCB-J in mice. (a) Population-based curve of intact [¹¹C]UCB-J in plasma of healthy wild-type (WT) and diseased (model of Huntington's disease, HD) mice. n = 3 per genotype at each time point. (b) Sigmoid fitting curve of the intact [¹¹C]UCB-J in WT mice. (c) Comparison of representative image-derived input functions (IDIF) corrected and uncorrected for the population-based sigmoid fitting of intact [¹¹C]UCB-J. Scatter plots between V_{T (IDIF)} (Logan) corrected and uncorrected for the population-based sigmoid fitting of intact [¹¹C]UCB-J based on a total of five WT mice (d) and correlations for each individual WT mouse (e) in different brain regions. Individual animals presented different regression line equations.