Comparative Evaluation in Nonhuman Primates of Five PET Radiotracers for Imaging the Serotonin Transporters: [11C]McN 5652, [11C]ADAM, [11C]DASB, [11C]DAPA, and [11C]AFM

Abstract

The recent introduction of a number of new radiotracers suitable for imaging the serotonin transporters (SERT) has radically changed the field of SERT imaging. Whereas, until recently, only one selective SERT radiotracer was available ([11C]McN 5652) for SERT imaging with positron emission tomography (PET), several new C-11-labeled radiotracers of the -dimethyl-2-(arylthio)benzylamine class have been described as appropriate imaging agents for the SERT. The aim of this study was to conduct a comparative evaluation of four of the most promising agents in this class ([11C]ADAM, [11C]DASB, [11C]DAPA, and [11C]AFM) with the reference tracer [11C]McN 5652 under standardized experimental conditions. This evaluation included in vitro measurements of affinity and lipophilicity, and in vivo PET imaging experiments in baboons. In vitro, DASB displayed significantly lower affinity for SERT than the other four tracers. In the blood, [11C]DASB and [11C]AFM display faster clearance and higher free fractions. Brain uptake was analyzed with kinetic modeling using a one-tissue compartment model and the metabolite-corrected arterial input function. The kinetic uptake of [11C]DASB was significantly faster compared with the other compounds, and the scan duration required to derive time-independent estimates of regional distribution volumes was shorter. [11C]DAPA exhibited the slowest brain kinetic. Regional-specific-to-nonspecific equilibrium partition coefficient (V3") was the highest for [11C]AFM, followed by [11C]DASB and [11C]DAPA, which in turn provided higher V3" values than [11C]ADAM and [11C]McN 5652. From these experiments, two ligands emerged as superior radiotracers that provide a significant improvement over [11C]McN 5652 for PET imaging of SERT: [11C]DASB, because it enables the measurement of SERT availability in a shorter scanning time, and [11C]AFM, because its higher signal-to-noise ratios provide a more reliable measurement of SERT availability in brain regions with relatively low density of SERT, such as in the limbic system.

Imaging the effects of genetic polymorphisms on radioligand binding in the living human brain: A review on genetic neuroreceptor imaging of monoaminergic systems in psychiatry

“…One major factor is obviously the quality of the imaging methods applied. [ Huang et al, 2002;Szabo et al, 2002). Moreover, there are several aspects other than genetic ones that have been shown to influence or associate with serotonin transporter binding.…”

“…As of yet, the effects of the 5-HTTLPR polymorphism have been studied with two ligands, [ 11 C]-(+)-6beta-(4-Methylthiophenyl)-1,2,3,5,6alpha,10beta-hexahydropyrrolo[2,1-a]isoquinoline ([ 11 C]McN 5652; Suehiro et al, 1993) and [ 11 C]-3-amino-4-(2-dimethylaminomethylphenylthio)benzonitrile ([ 11 C]DASB; Wilson et al, 2000;Houle et al, 2000;Wilson and Houle, 1999). [ 11 C]DASB is currently the method of choice for PET imaging of the 5-HTT, and it has been shown to be superior to [ 11 C]McN 5652 in several instances (Frankle et al, 2004;Huang et al, 2002;Szabo et al, 2002).…”

A radiometabolite study of the serotonin transporter PET radioligand [11C]MADAM

“…However, as shown in Figures 4A [31] and a high initial uptake in lung tissue may also explain the relatively slow distribution of SERT radioligands to brain. More over, this large concentration is correlated with the relative high lipophilicity of SERT radioligands in a range from 2.4 to 3.3 [32].…”

Radiotherapy Planning

“…Randomized data have demonstrated the role of FDG/ PET in the staging of early stage lung cancer and may significantly change the staging and treatment plan, often upstaging the disease revealing regional lymph node metastases or distant metastases. [54][55][56] Integrating PET/CT into radiotherapy planning can alter the target volumes when compared with CT-based volumes and also reduce interuser variability of target volume delineation. 57 In a prospective study of 91 consecutive patients, with non-small cell lung carcinoma from 2003 to 2008, undergoing radiation therapy, PET imaging provided additional diagnostic information over CT alone in 20%, leading to upstaging in 17% and alterations in the PTV and subsequent treatment planning in 9%.…”