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. VT (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 K1 (IDIF). A scan duration of 60 min was sufficient for reliable VT (IDIF) and K1 (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.

Automated radiosynthesis of [11C]UCB‐J for imaging synaptic density by positron emission tomography

“…In our hands, in situ preparation of boronic acid worked sluggishly (Table and Table S1). Based on the method developed by Onega et al, hydrochloric acid was employed and reaction progress monitored by the liquid chromatography‐mass spectrometry (LCMS) using HCl in different solvents. The application of HCl in dioxane gave none of the desired boronic acid 4 (entry 1).…”

“…The radiosynthesis of [ 11 C]UCB-J is based on the application of the palladium(0)-mediated Suzuki cross-coupling reaction between the carbon-11 methyliodide ([ 11 C]CH 3 I) and trifluoroborate precursor 3 (Figure 1). 7,10,11,13,14 Initially explored method employed a more common Suzuki reacting partner, ie, the corresponding boronic acid 15 (eg, 4 in Scheme 1) as a radiolabelling precursor; however, the boronic acid precursor 4 proved to be unstable upon storage resulting in poor reproducibility and unreliable radiochemical yields. Further investigation indicated that while trifluoroborate 3 can be used as a radiolabelling precursor for [ 11 C]UCB-J, the actual reacting specie is the boronic acid, thus necessitating a need for a mixture of trifluoroborate 3 and 3-10% of the boronic acid 4 to be present in the reaction vessel.…”

“…Further investigation indicated that while trifluoroborate 3 can be used as a radiolabelling precursor for [ 11 C]UCB-J, the actual reacting specie is the boronic acid, thus necessitating a need for a mixture of trifluoroborate 3 and 3-10% of the boronic acid 4 to be present in the reaction vessel. 11,14 While the application of the mixture improved reproducibility of the method, it made it non-GMP compliant for which reason Onega and coworkers 11 developed an improved protocol whereby the boronic acid was formed in situ by treatment of trifluoroborate 3 with 1M HCl (Scheme 1).…”

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

“…For this reason, we generated a population-based metabolite curve in order to adjust for the peripheral metabolism and to validate the applicability of a noninvasive IDIF over the metabolite-corrected plasma input function. A limitation in the use of a population-based correction is the need of high inter-individual reproducibility; otherwise, under-or overestimations in the quantification may be introduced since the same curve is applied to all the subjects as we recently reported for the radioligand [ 11 C]UCB-J [13]. Since correcting the noninvasive IDIF for metabolism did not improve the agreement to V T (AV shunt, Corr) , we will use the uncorrected IDIF as noninvasive input function.…”

“…In order to generate a population-based metabolite correction to account for peripheral radiometabolism, we measured parent fractions in a cohort of WT mice (n = 3 per time point) at 5, 15, and 30 min p.i. The procedure was done adapting the previously described methodology [13] to [ 11 C]ITDM. Details of the procedure are provided in the ESM.…”