Tracer Kinetic Modeling of [¹¹C]AFM, a New PET Imaging Agent for the Serotonin Transporter

Abstract

11 C]2-[2-(dimethylaminomethyl)phenylthio]-5-fluoromethylphenylamine, is a new positron emission tomography (PET) radioligand with high affinity and selectivity for the serotonin transporter (SERT). The purpose of this study was to determine the most appropriate kinetic model to quantify [11 C]AFM binding in the healthy human brain. Positron emission tomography data and arterial input functions were acquired from 10 subjects. Compartmental modeling and the multilinear analysis-1(MA1) method were tested using the arterial input functions. The one-tissue model showed a lack of fit in low-binding regions, and the two-tissue model failed to estimate parameters reliably. Regional time-activity curves were well described by MA1. The rank order of INTRODUCTIONThe serotonin transporter (SERT) is located on the presynaptic terminals of neurons, and is responsible for the reuptake of serotonin, a neurotransmitter involved in the regulation of brain functions such as mood, appetite, and sleep.1 Serotonin transporter is a primary target of action for selective serotonin reuptake inhibitors, which are effective therapeutic agents for the treatment of major depressive disorder, obsessive-compulsive disorder, posttraumatic stress disorder, and other mood and anxiety disorders. Because the serotonin system has such an important role in the pathophysiology of these diseases, there has been considerable interest in developing in vivo positron emission tomography (PET) radioligands for imaging SERT distribution. In the human brain, highest concentrations of SERT are found in the raphe nucleus and midbrain, followed by thalamus, striatum, and amygdala. Intermediate levels are in the limbic system (hippocampus and cingulate cortex), and lower levels in the neocortex regions, with cerebellum displaying lowest to negligible SERT density.

Synaptic Changes in Parkinson Disease Assessed with in vivo Imaging

“…Secondary (exploratory) regions included the ventral striatum, thalamus, amygdala, hippocampus, insula, anterior and posterior cingulum, and dorsolateral prefrontal, orbitofrontal, ventromedial prefrontal, parietal, temporal, and occipital cortices. The ROIs above were taken from the Anatomical Automatic Labeling for SPM2 (AAL) atlas with the exception of hand‐drawn templates in the following areas: the SN, which was defined with a dopamine tracer, the locus coeruleus, defined with a norepinephrine tracer, and the raphe nucleus, which was defined with a serotonin tracer, as these tracers show high uptake in the respective areas that are not defined in AAL. ROI delineation was described in more detail in previous work, but briefly, the SN was drawn on 5 to 7 coronal slices for approximately a 1ml volume and the other non‐AAL ROIs were confirmed on the Talairach and Tournoux atlas .…”

Optimization of the k2′ Parameter Estimation for the Pharmacokinetic Modeling of Dynamic PIB PET Scans Using SRTM2

“…Previous studies using SRTM2 for pharmacokinetic modeling employed different approaches for k ′ 2 estimation. For example, this parameter was evaluated by coupling all target time activity curves for radiotracers designed for D2/D3 receptors [17,18] and radioligands with a high affinity for the serotonin transporter [19]. Tracers such as [ 11 C]P943 [20], used for quantifying serotonin 5-HT1B receptors, use the median value of the k ′ 2 estimation for all voxels that have a BP SRTM ND value between 0.5 and 4, and [ 18 F]DPA-714 [21], used for neuroinflammation, the median of all k ′ 2 values from all voxels in the image.…”

Direct reconstruction of parametric images for brain PET with event-by-event motion correction: evaluation in two tracers across count levels

“…The 1T model has been validated for use in both [ 11 C]AFM and [ 11 C]UCB-J, though some lack of fit was observed for [ 11 C]AFM in regions with relatively low binding [21]. If the regions with poor fits are indeed only those with low activity, the relative magnitude of the residuals due to lack of fit will also likely be low, and error propagation is expected to be minimal.…”

“…Here, we evaluate the performance of this algorithm for two tracers whose kinetics can be modeled with the1-tissue compartment (1T) model, [ 11 C]AFM and [ 11 C]UCB-J. [ 11 C]AFM [21] targets the serotonin (5HT) transporter protein (SERT) and has been applied to the study of psychiatric disorders such as depression and post-traumatic stress disorder. [ 11 C]UCB-J is a new tracer targeting the synaptic vesicle glycoprotein 2A [22] and can be used to measure synaptic density, relevant to a wide range of diseases including epilepsy and Alzheimer’s disease.…”