Imaging the serotonin transporter with positron emission tomography: initial human studies with [11C]DAPP and [11C]DASB

Abstract

Two novel radioligands, N,N-dimethyl-2-(2-amino-4-methoxyphenylthio) b enzylamine (DAPP) and (N,N-dimethyl-2-(2-amino-4-cyanophenylthio) benzylamine (D ASB), were radiolabeled with carbon-11 and evaluated as in vivo probes of the serotonin transporter (SERT) using positron emission tomography (PET). Both compounds are highly selective, with nanomolar affinity for the serotonin transporter and micromolar affinity for the dopamine and norepinephrine transporters. Six volunteers were imaged twice, once with each of the two radioligands. Both ligands displayed very good brain penetration and selective retention in regions rich in serotonin reuptake sites. Both had similar brain uptake and kinetics, but the cyano analogue, [11C]DASB, had a slightly higher brain penetration in all subjects. Plasma analysis revealed that both radiotracers were rapidly metabolized to give mainly hydrophilic species as determined by reverse-phase high-performance liquid chromatography. Inhibition of specific binding to the SERT was demonstrated in three additional subjects imaged with [11C]DASB following an oral dose of the selective serotonin reuptake blocker citalopram. These preliminary studies indicate that both these substituted phenylthiobenzylamines have highly suitable characteristics for probing the serotonin reuptake system with PET in humans.

PET Imaging of Serotoninergic Neurotransmission with [11C]DASB and [18F]altanserin after Focal Cerebral Ischemia in Rats

“…10 Positron emission tomography (PET) with [ 11 C]DASB and [ 18 F]altanserin has widely been used to investigate the availability of serotonin transporter (SERT) and serotonin receptor 5-HT 2A in both humans and animals. [11][12][13][14] This imaging method has proven to be helpful in elucidating the role of serotoninergic mechanisms in aging, 15 and neurologic and psychiatric pathologies such as Alzheimer's disease, 16 depression 17,18 obsessive-compulsive disorder, 19 bipolar disorder, 20 and schizophrenia. 21 Nevertheless, the role of serotoninergic neurotransmission in stroke evolution using PET imaging has scarcely been explored to date.…”

Quantitative PET Studies of the Serotonin Transporter in MDMA Users and Controls Using [11C]McN5652 and [11C]DASB

“…Recent studies in baboons (Szabo et al, 2002) and humans (Frankle et al, 2004;Houle et al, 2000;Meyer et al, 2001;Wilson et al, 2000) have demonstrated the suitability of a new SERT ligand, [ 11 C]DASB, for studying serotonin neurons in the living brain. [ 11 C]DASB appears to have two critical advantages over [ 11 C]McN5652, including a greater specific-to-nonspecific equilibrium activity ratio, and a measurable plasma-free fraction for use in tracer modeling (Frankle et al, 2004).…”

Quantification of Ligand PET Studies using a Reference Region with a Displaceable Fraction: Application to Occupancy Studies with [11C]-DASB as an Example

“…11 C]-DASB is a highly selective ligand for SERT, not only with nanomolar affinity for the SERT but also with micromolar affinity for the dopamine and norepinephrine transporters (Houle et al, 2000). In cerebellum, the reference region of choice for this tracer, a displaceable fraction of up to 33% has been demonstrated after acute sertraline treatment (Parsey et al, 2006).…”