Compartmental Modeling of 11C-HOMADAM Binding to the Serotonin Transporter in the Healthy Human Brain

Alterations in the neurotransmitter serotonin have been implicated in several neurologic disorders, including depression, schizophrenia, Alzheimer’s disease, and Parkinson’s disease (1–3). Serotonin receptors and transporters are concentrated primarily in the raphe nucleus bodies of the brain stem and populate areas such as the thalamus, striatum, cingulate cortex, and cerebral cortex (4,5). Very high-density serotonin transporter (SERT) expression is observed in the thalamus, midbrain, and striatum; moderate-density expression is seen in the amygdalae and cingulated cortex; and lower-density expression is seen in the neocortical regions, including the cerebellum. The SERT concentration in cell bodies of the presynaptic serotoninergic neurons is an indicator of terminal viability and integrity (6–8). Therefore, SERT represents a specific marker of serotoninergic neuron density permitting quantitative mapping in vivo by PET with highly specific radiotracers. These highly specific radioligands have the potential to reveal regional brain distributions of SERT in various states of mood, disease, and treated and untreated conditions. Several high-affinity ligands have been developed and introduced into humans to map SERT distributions in the central nervous system (9–11). Of these, 11C-3-amino-4-(2-dimethylaminomethyl-phenylsulfanyl)-benzonitrile (11C-DASB) and trans-1,2,3,5,6,10-s-hexahydro-6-[4-(methylthio)phenyl]pyrrolo-[2,1-a]-isoquinoline (11C-McN 5652) have been extensively studied and have been found to accumulate in SERT-rich regions of the brain stem, midbrain, and striatum. Compared with the more recently developed 11C-N,N-dimethyl-2-(2-amino-4-methylphenylthio)benzylamine (11C-MADAM) (10), both of these tracers exhibit moderately high free uptake and nonspecific binding (12–14), as indicated by the high total distribution volume (VT) in the cerebellum. The presence of nonspecific uptake may present difficulties in the delineation of small structures, such as the raphe nuclei, or in comparisons of cortical regions with low SERT densities. The low nonspecific binding of 11C-MADAM is potentially advantageous for these reasons, but equilibrium occurs late, with peak radioactivity levels occurring between 30 and 60 min after injection. 11C-5-bromo-2-[2-(dimethylaminomethylphenylsulfanyl)]phenylamine (11C-DAPA) and 11C-2-[2-(dimethylaminomethyl)phenylthio]-5-fluoromethylphenylamine (11C-AFM) are 2 other recently synthesized SERT ligands; compared with 11C-DASB and 11C-McN-5652, they have higher ratios of specific binding to nonspecific binding. However, to date, studies with these 2 ligands have been conducted only with primate models (15). Jarkas et al. reported on the labeling of N,N-dimethyl-2-(2′-amino-4′-hydroxymethylphenylthio)benzylamine (HO-MADAM) with 11C, a highly specific SERT imaging agent (16). Preliminary studies characterizing the tracer kinetics in vivo in a male rhesus monkey revealed rapid binding kinetics, high uptake in the midbrain and thalamus, moderate uptake in the brain stem and pons, and low uptake in the cerebellum. High ratios of specific binding to nonspecific binding were reported, with thalamic-to-cerebellum, midbrain-to-cerebellum, and cortical-to-cerebellum ratios being higher than those of 11C-DASB (15,16). In addition, the time to peak radioactivity levels in SERT-rich regions was shorter with this tracer than with 11C-DASB and 11C-AFM. Quasi-equilibrium was subsequently reached at 22–45 min in regions of the thalamus and midbrain; the corresponding values for 11C-DASB and 11C-AFM were 65 and 85 min, respectively. The higher concentration of 11C-HOMADAM in the subcortical regions of the brain than in the cerebellum and its rapid kinetics are attractive characteristics and are the reasons for further investigation. The aim of this work was to use 11C-HOMADAM uptake data from 8 healthy human subjects to evaluate whether SERT density can be reliably measured. We present quantitative modeling with measured arterial plasma radioactivity in 2- and 4-parameter compartment models and with a reversible-binding graphic method. In addition, a simplified compartment model and the graphic method were evaluated with reference tissue as the input.