Quantification of synaptic density with [11C]UCB-J PET

Finnema et al (2016) demonstrated that [11C]UCB-J can be used as synaptic density marker in humans. [11C]UCB-J binds to synaptic vesicle glycoprotein 2A (SV2A), which is ubiquitously and homogeneously located in synapses across the brain (Bajjalieh et al., 1994; Janz & Südhof, 1999). [11C]UCB-J could be displaced by Levetiracetam, which is a SV2A-selective drug; this confirms that [11C]UCB-J is specifically binding to SV2A (Finnema et al., 2016). PET imaging of patients with temporal lobe epilepsy revealed unilateral decreased binding, suggesting that [11C]UCB-J can be used to detect synaptic loss in vivo in human subjects (Finnema et al., 2016). In addition, [11C]UCB-J can be used to assess occupancy of SV2A binding drugs (Nicolas et al., 2016).

The brain uptake of [11C]UCB-J is highest in the striatum and cortex, and moderate in the thalamus and cerebellum, and low in white matter (Finnema et al., 2016 and 2018).

[11C]UCB-J has favourable dosimetry (Nabulsi et al., 2016) and excellent test-retest variability (Finnema et al., 2018). Binding is specific; only ∼20% of the volume of distribution (VT) of [11C]UCB-J is due to the nondisplaceable binding (VND); therefore VT can be used as outcome parameter (Rabiner, 2018), representing the SV2A concentration in the brain.

Blood data

Plasma free fraction (fp), the fraction of tracer not bound to plasma proteins, was 0.32 (range 0.29-0.34) in the test-retest study of five human volunteers (Finnema et al., 2018).

The fraction of unmetabolized radioligand drops to ∼0.3 in 20 minutes after injection, and after that the fraction drops only slowly, being >0.2 at 120 min p.i. (Finnema et al., 2018; figure 1). Individual variation in fractions seems to be high, probably preventing the usage of population average. Finnema et al. (2018) fitted an inverted integrated gamma function to the unmetabolized parent fraction data.

As an alternative to arterial blood sampling, extraction of image-derived input function could be feasible, as such method has been applied to [18F]UCB-H (Bahri et al., 2017); the method still required blood samples for metabolite correction and scaling.

Brain data analysis methods

Peak radioactivity concentration in the plasma is about two times higher than the peak radioactivity in the brain; thus the vascular radioactivity can be neglected in compartmental model analysis, but it may have an impact in time delay correction (Finnema et al., 2018).

Based on AIC, the two-tissue compartmental model (2TCM) fitted the regional data better than the one-tissue compartmental model (1TCM), but the difference in VT estimates was small; additionally, 2TCM did not provide reasonable parameter values for some data sets, and therefore 1TCM was selected for the final data analysis (Finnema et al., 2018). Mean VT ranged from 5.3 ± 0.5 in the centrum semiovale to 22.4 ± 1.8 in the putamen (Finnema et al., 2018).

Parametric VT images can be calculated using 1TCM with basis functions method, with k2 limits set to 0.01-1.0 min-1 (Finnema et al., 2018). Highest VT, 34±4, was seen in parietal cortex (Chen et al., 2018). Parametric image of K1, representing perfusion and delivery, can also be produced simultaneously; the pattern of K1 reduction in AD patients is similar to the pattern of hypometabolism in AD seen with [18F]FDG (Chen et al., 2018).

Finnema et al. (2018) assessed the time stability of the 1TCM , and noticed that the study length could be reduced from 120 to 60 min with no impairment in ICC or test-retest variability. Shorter scan duration will lead to somewhat lower VT estimates (maximally about -5% when comparing 60 min and 120 min scan lengths), but there is also possibility that the longer scan duration may lead to overestimated VT due to uptake of radioactive metabolite(s) in the brain, especially in the low uptake regions.

Correction of VT for plasma protein binding (VT/fp) worsened ICC and test-retest variability, and thus Finnema et al. (2018) recommended that VT/fp would be used as outcome parameter only in cross-sectional studies, if group differences or treatment effects in plasma protein binding could be expected.

Ubiquitous distribution of SV2A means also that there is no true reference region in the brain that could be used as input function or to determine the SV2A binding potential. Therefore arterial input function must be measured, and VT is the only possible quantitative parameter; because of the relatively low nonspecific binding (VNS) of [11C]UCB-J in the brain VT can be assumed to well represent the SV2A density. Yet, for comparative studies where strict quantification is not necessary, centrum semiovale, that has low uptake of SV2A ligands, can be used as reference region in [11C]UCB-J data analysis, applying either SRTM or one-tissue compartmental model based DVR (Finnema et al., 2016; Toyonaga et al., 2018), or 60-90 min tissue-to-reference ratio (Naganawa et al., 2018). VT in the centrum semiovale was virtually identical between AD patients and age matched control subjects (Chen et al., 2018). Highest BPND, 6.09±0.33 in control subjects, was seen in parietal cortex (Chen et al., 2018).



References:

Chen M, Mecca AP, Naganawa M, Finnema SJ, Toyonaga T, Lin S, Najafzadeh S, Ropchan J, Lu Y, McDonald JW, Michalak HR, Nabulsi NB, Arnsten AFT, Huang Y, Carson RE, van Dyck CH. Assessing synaptic density in Alzheimer disease with synaptic vesicle glycoprotein 2A positron emission tomographic imaging. JAMA Neurol. 2018 (in press). doi: 10.1001/jamaneurol.2018.1836.

Finnema SJ, Nabulsi NB, Eid T, Detyniecki K, Lin S, Chen M-K, Dhaher R, Matuskey D, Baum E, Holden D, Spencer DD, Mercier J, Hannestad J, Huang Y, Carson RE. Imaging synaptic density in the living human brain. Sci Transl Med. 2016; 8: 348ra96. doi: 10.1126/scitranslmed.aaf6667.

Finnema SJ, Nabulsi NB, Mercier J, Lin SF, Chen MK, Matuskey D, Gallezot JD, Henry S, Hannestad J, Huang Y, Carson RE. Kinetic evaluation and test-retest reproducibility of [11C]UCB-J, a novel radioligand for positron emission tomography imaging of synaptic vesicle glycoprotein 2A in humans. J Cereb Blood Flow Metab. 2018; 38(11): 2041-2052. doi: 10.1177/0271678X17724947.

Löscher W, Gillard M, Sands ZA, Kaminski RM, Klitgaard H. Synaptic vesicle glycoprotein 2A ligands in the treatment of epilepsy and beyond. CNS Drugs 2016; 30(11): 1055-1077.

Nabulsi NB, Mercier J, Holden D, Carré S, Najafzadeh S, Vandergeten MC, Lin SF, Deo A, Price N, Wood M, Lara-Jaime T, Montel F, Laruelle M, Carson RE, Hannestad J, Huang Y. Synthesis and preclinical evaluation of 11C-UCB-J as a PET tracer for imaging the synaptic vesicle glycoprotein 2A in the brain. J Nucl Med. 2016; 57(5): 777-784. doi: 10.2967/jnumed.115.168179.

Rabiner EA. Imaging synaptic density: a different look at neurological diseases. J Nucl Med. 2018; 59(3): 380-381. doi: 10.2967/jnumed.117.198317.



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Created at: 2017-11-29
Updated at: 2018-11-02
Written by: Vesa Oikonen