This study explores the feasibility of imaging SV2A in the spinal cord with [11C]UCB-J PET. Firstly, baseline and blocking PET data were simulated using previously defined SV2A concentrations in the SC relative to the cortex of ~ 20% [14], conditions of 75% blocking, and the partial volume effect. Given a true VND of 2.8 mL/cm3 [16], and assuming no specific binding in the WM, calculated baseline and blocking VT values were 3.09 and 2.36 mL/cm3, respectively, with an observed VND of 2.12 mL/cm3. The simulation suggested that specific binding of [11C]UCB-J in the spinal cord is low, with an expected BPND of 0.46. Next, we evaluated specific [11C]UCB-J binding in the cSC under baseline and blocking conditions from scans acquired in four human subjects on the HRRT. The observed VT, VND, and VS values agreed exceptionally well with the simulated measures, with an expected BPND value of 0.43. Lastly, we explored the feasibility of full SC imaging using whole body [11C]UCB-J PET/CT images acquired on the mCT. CT images were used to automatically define ROIs for the full, cervical, and thoracic SC. DVR estimates in these regions show that [11C]UCB-J uptake in the full SC relative to cortical GM is 0.115. Interestingly, a higher DVR was observed in the cSC than in the tSC, with DVRs of 0.145 and 0.112, respectively. The DVR in the cSC agreed well with the ratio of baseline VT in the SC relative to the brain, with a ratio of approximately 0.154 from the HRRT study. Although the pattern of heterogeneity within the SC has not been well established in the synaptic density literature, it is the same pattern that has been reported in [18F]FDG images of the human spinal cord as imaged with PET/CT and PET/MRI [23,24,25,26]. The consistency across imaging methods in this study suggests that SV2A may be imaged in the human SC, but [11C]UCB-J may not be an ideal PET tracer to use for this purpose, due to its low specific binding.

The current study implemented PET data acquired across two different scanners—the Siemens HRRT for brain/cSC imaging and the Siemens Biograph mCT for full SC imaging—each with different spatial resolutions. For each set of images, the whole SC ROIs were defined in different ways. On the HRRT images, the cSC ROI was defined on an early PET image. On the mCT images, the SC was defined based on the CT image. For both cases, the ROI included the whole SC, consisting of GM in the center of the cord surrounded by WM. A vast majority of the specific SV2A signal is located at the center of the ROI in the GM, with low-to-negligible concentrations of SV2A in the WM. Because of this, the effect of the resolution difference across the two scanners will likely be small, and the PVE caused by the respective spatial resolutions should not drastically affect our quantitation of the SC. Any activity that may spill over from the high activity GM voxels will spill into the relatively low activity WM voxels, which are also included in the SC ROI. The results presented in this work support this premise, particularly in regards to the similarities of SV2A PET measures in the cSC across images of different resolution.

However, PVE may be of importance given different SV2A concentrations and potential differences in radiotracer properties between GM and WM in the SC. The cross section of the SC, including both WM and GM, is elliptical with diameters of about 9 mm in the anteroposterior direction and 12 mm in the transverse direction in the cervical segment and diameters of 6 mm and 9 mm, respectively, in the thoracic segments [27]. Since the human spinal cord is approximately 75% WM by volume [15], if the cross-sectional area of the full cSC is ~ 84.8 mm2, then approximately ~ 21.2 mm2 or 25% of the full cSC volume will be comprised of GM. Given a PET system with resolution at about 4–5 mm, isolating GM signal from the full cord is impossible without the use of partial volume correction. Of the many advantages to PET/MR imaging in the spinal cord [28], MR images can aid in partial volume correction to isolate PET signals from the spinal cord, the CSF and other surrounding tissues. With fine enough resolution on the MRI, distinction of the GM and WM in the spinal cord may be possible, but this was not feasible with the MRIs acquired for brain images in the current study. In addition, the contrast of GM to WM signal of [11C]UCB-J is much lower than what is observed in the brain, due to a lower SV2A concentration in SC, as has been reported in rodents [14]. This lower GM/WM contrast will reduce the potential degree of PVE observed within the SC.

In analyzing the in vivo occupancy study of SV2A in the cSC, the VT estimates at baseline and blocking conditions were estimated using 1-tissue compartment model fitting of cSC TACs. ROIs of the cSC were located at the axial edge of the HRRT FOV (since the brain was centered), which has lower sensitivity for gamma ray detection due to smaller solid angle available at this positioning inside the PET scanner. In addition to higher noise, out of field scatter can affect the image quality and quantitation at this location, potentially leading to inaccuracies in the estimates presented here. In the whole-body images, the tSC is particularly sensitive to scatter correction accuracy due to the proximity to the liver, which has very high [11C]UCB-J uptake. Inaccurate scatter correction in this region of the image would lead to misestimation of radioactivity concentration in the tSC. In addition to scatter, subject motion may also have an effect on the quantitation of PET radioactivity, particularly in the case of respiratory motion in whole body PET images. Furthermore, using PSF modeling with OSEM image reconstruction methods may increase potential edge or Gibbs artifacts that cause quantitative inaccuracies in PET images, in a manner that is dependent on number of iterations, pixel size, and object size [29]. The effects of these limitations should be explored further, to confirm the current study reports of ~ 20% lower [11C]UCB-J DVR in the tSC. In any case, blocking studies in whole body scanning (with arterial blood sampling) may aid in evaluation of specific SV2A binding and VND throughout the full SC.

Although it is part of the central nervous system, the spinal cord differs from the brain particularly in their interaction with circulation. In the brain, the blood–brain barrier (BBB) is a layer of endothelial cells that surround blood vessels in the brain, which have unique characteristics such as lacking fenestrations in cell membranes and tight junctions between cells. The BBB regulates transport of molecules from circulation into brain tissue, particularly keeping larger and more polar particles from entering the brain tissues. Similar to those in brain, blood vessels in the spinal cord have a blood-spinal cord barrier (BSCB), though it is believed that the BSCB may be more permeable than the BBB [30]. This may be of particular interest given that previous studies have suggested that radiometabolites of [11C]UCB-J do not pass the BBB [19], but uptake of radiometabolites in the SC tissue is not yet well studied, and may be possible depending on the size or polarity of radiometabolites as well as the permeability of the BSCB. The current study uses 60 min of dynamic PET data to evaluate [11C]UCB-J uptake in both cSC images from the HRRT and full SC images on the mCT, which limits the potential effects on the PET measures of radiometabolites, which tend to increase in relative concentration throughout the scan.

Furthermore, there is another difference between the brain and SC that is important to note, especially when using reference tissue methods to quantify PET images of the SC as implemented here. The current study defined a SC ROI that included both GM and WM, while the reference region utilized with SRTM2 was comprised of whole brain GM only. Previous work using [11C]UCB-J has reported lower K1 estimates in WM than in GM regions of the brain [19]. Given that the SC is a majority WM by volume, the K1 relative to the brain GM, or the R1 estimate, may be low due to this difference. This is likely the reason why the R1 estimates that resulted from SRTM2 analysis of the whole-body full SC were low, on the scale of about 0.2 (Table 3). This should be considered when using reference region quantification methods in the future study of SC PET imaging.

Although the results presented in this study are somewhat encouraging, there is additional work that can be done to validate or improve our findings. For example, ex vivo experiments may be completed to confirm SV2A density throughout the cervical, thoracic or full SC. Our group has completed preliminary Western blotting experiments to investigate the concentration of SV2A in the cSC compared to SV2A in gray matter regions of one 13 y.o. male rhesus monkey. The resulting SC/brain SV2A ratio, equivalent to a VS ratio (assuming no difference in Kd), was about 0.057. Given that SV2A density may be up to fivefold lower in the GM of the SC compared to that of the cortex, and that only 25% of the SC is comprised of GM, this ratio strongly agrees with an estimated relative SV2A concentration in the SC of 0.2(0.25) = 0.05. Using the VS estimates from our brain imaging data reported in Tables 1 and 2, we report a SC/brain VS ratio of approximately 0.056. Further studies are needed to explore if, and to what extent, SV2A changes throughout the length of the spinal cord.

SV2A image quality in the SC may be enhanced by improving PET scanner resolution. Given the dimensions of the SC, a PET system with ~ 3 mm resolution or better is crucial for successful imaging of the SC. SV2A PET radiotracers labeled with fluorine-18, such as [18F]SynVesT-1 [31], will result in higher quality PET images due to lower statistical noise. Furthermore, new radiotracers with less metabolism, or radiotracers with affinity greater than that of [11C]UCB-J(Kd <  ~ 3 nM) may also improve the quantification of SV2A PET in the spinal cord. As described above, the Bmax in the full SC is expected to be ~ 20-fold lower than the cerebral cortex. To get a more useful measure of BPND (i.e., ~ 5 times greater than the BPND estimates of ~ 0.45 in the current study), the Kd of an SV2A radioligand should be at least 5 times lower than that of [11C]UCB-J (assuming no change in nondisplaceable uptake). Furthermore, additional radioligands that target other proteins or physiological functions of interest aside from SV2A, such as the serotonin transporter with [11C]AFM [32] or the 18 kDa translocator protein (TSPO) with [11C]PK11195 [33] or [18F]GE-180 [34], may be worthwhile in characterizing spinal cord pathophysiology.

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