In Vivo Quantification of Human Serotonin 1A Receptor Using ¹¹C-CUMI-101, an Agonist PET Radiotracer

Abstract

The serotonin (5-hydroxytryptamine, or 5-HT) type 1A receptor (5-HT1AR) is implicated in the pathophysiology of numerous neuropsychiatric disorders. We have published the initial evaluation and reproducibility in vivo of [O-methyl-11C]2-(4-(4-(2-methoxyphenyl)piperazin-1-yl)butyl)-4-methyl-1,2,4-triazine-3,5 (2H,4H)dione (11C-CUMI-101), a novel 5-HT1A agonist radiotracer, in Papio anubis. Here, we report the optimal modeling parameters of 11C-CUMI-101 for human PET studies. Methods PET scans were obtained for 7 adult human volunteers. 11C-CUMI-101 was injected as an intravenous bolus, and emission data were collected for 120 min in 3-dimensional mode. We evaluated 10 different models using metabolite-corrected arterial input functions or reference region approaches and several outcome measures. Results When using binding potential (BPF = Bavail/KD [total available receptor concentration divided by the equilibrium dissociation constant]) as the outcome measure, the likelihood estimation in the graphical analysis (LEGA) model performed slightly better than the other methods evaluated at full scan duration. The average test–retest percentage difference was 9.90% ± 5.60%. When using BPND (BPND = fnd × Bavail/KD; BPND equals the product of BPF and fnd [free fraction in the nondisplaceable compartment]), the simplified reference tissue method (SRTM) achieved the lowest percentage difference and smallest bias when compared with nondisplaceable binding potential obtained from LEGA using the metabolite-corrected plasma input function (r2 = 0.99; slope = 0.92). The time–stability analysis indicates that a 120-min scan is sufficient for the stable estimation of outcome measures. Voxel results were comparable to region-of-interest–based analysis, with higher spatial resolution. Conclusion On the basis of its measurable and stable free fraction, high affinity and selectivity, good blood–brain barrier permeability, and plasma and brain kinetics, 11C-CUMI-101 is suitable for the imaging of high-affinity 5-HT1A binding in humans.

Model-Free Quantification of Dynamic PET Data Using Nonparametric Deconvolution

“…Four previously acquired test-retest datasets were considered: 12 scans with CUMI, 14 20 with DASB, 15 14 with PE2I, 16 and 10 with WAY. 17 The studies were performed in accordance with the Declaration of Helsinki and The Institutional Review Boards of Columbia University Medical Center and New York State Psychiatric Institute approved the protocol.…”

“…15 For the 2TCM, we used the metabolitecorrected input function measured in one of the considered CUMI scans, a tracer whose kinetics is well described by a 2TCM, 14 and set the K 1 to k 4 values in five selected regions (cerebellar gray matter, hippocampus, temporal lobe, occipital lobe, and cingulate) based on existing data on CUMI healthy control subjects. 14 In both cases, we simulated Gaussian noise with zero mean and standard deviation (SD) calculated as SD(t i ) = α. σ/w(t i ), where w(t i ) is the root square of the duration of the time frame during which the PET data corresponding to time t i has been acquired, and σ indicates the level of noise that we derived from the weighted residual sum of square values obtained by fitting DASB and CUMI scans, respectively, with CMs. Increasing α allows us to study the various estimation techniques in situations with proportionately more noise than what we encounter in our real-data situations.…”

Identifying serotonergic mechanisms underlying the corticolimbic response to threat in humans

“…A PET radiotracer sensitive to in vivo serotonin levels, analogous to the usefulness of [ 11 C]raclopride for measuring endogenous dopamine release, is not currently available [85]. However, candidates for measuring endogenous serotonin release with promising results in both animals and humans are currently being evaluated [86][87][88]. Looking forward, the application of a PET radiotracer for modelling endogenous serotonin release in the context of a dual PET-MRI scanner offers the very exciting opportunity to evaluate the effects of threat-related corticolimbic brain function on serotonin release in real-time, offering still more effective ways of understanding how serotonin signalling modulates underlying neurobiological pathways.…”

Noninvasive Blood-Free Full Quantification of Positron Emission Tomography Radioligand Binding

“…1,12 A region meeting these criteria has not yet been identified, or might not exist, for many radioligands, [13][14][15][16][17][18] including [ 11 C]CUMI-101 (CUMI), a partial agonist of the serotonin 5-HT 1A receptor, which is implicated in the pathophysiology of numerous neuropsychiatric disorders. 3 Even if such a region exists, identification and validation can be difficult. Erroneously designating a region as a reference results in biased estimates of the PET outcomes, [19][20][21][22] and the validity of resulting conclusions may be called into question.…”

“…Positron emission tomography is an invaluable tool to establish the genetic and cellular basis of brain diseases. [1][2][3] Fully quantitative PET measures a series of binding potentials between radioligand and target to indirectly determine the available amount of the target. 1 These potentials are in various ways related to the density of available target (B max ) through the affinity of the radioligand for the available binding sites 1 (1/K D ).…”