5-HT radioligands for human brain imaging with PET and SPECT

Abstract

The serotonergic system plays a key modulatory role in the brain and is the target for many drug treatments for brain disorders either through reuptake blockade or via interactions at the 14 subtypes of 5-HT receptors. This review provides the history and current status of radioligands used for positron emission tomography (PET) and single photon emission computerized tomography (SPECT) imaging of human brain serotonin (5-HT) receptors, the 5-HT transporter (SERT), and 5-HT synthesis rate. Currently available radioligands for in vivo brain imaging of the 5-HT system in humans include antagonists for the 5-HT(1A), 5-HT(1B), 5-HT(2A), and 5-HT(4) receptors, and for SERT. Here we describe the evolution of these radioligands, along with the attempts made to develop radioligands for additional serotonergic targets. We describe the properties needed for a radioligand to become successful and the main caveats. The success of a PET or SPECT radioligand can ultimately be assessed by its frequency of use, its utility in humans, and the number of research sites using it relative to its invention date, and so these aspects are also covered. In conclusion, the development of PET and SPECT radioligands to image serotonergic targets is of high interest, and successful evaluation in humans is leading to invaluable insight into normal and abnormal brain function, emphasizing the need for continued development of both SPECT and PET radioligands for human brain imaging.

Figure 1

Six PET radioligand brain images in healthy control individuals, taken with different serotonergic markers. Transverse, sagittal, and coronal sections are shown. (A) 5-HTsynthesis. Normalized [¹¹C]AMT Trapping (K*), average image from 60 healthy controls. Image courtesy of P. Gravel, M. Leyton, M. Diksic and C. Benkelfat, McGill University Health Center (MUHC), Montreal, Canada. (B) 5-HT_1A receptor. HRRTPET image of [¹¹C]CUMI-101brain distribution, from Center for Integrated Molecular Brain Imaging (Cimbi), Copenhagen, Denmark. (C) 5-HT_1B receptor. Fused MR and PET images of [¹¹C]AZ10419369 brain distribution. Average images from 3 to 93 min after injection. Image courtesy of K. Varnäs, C. Halldin and L. Farde, Karolinska Institutet, Dept of Clinical Neuroscience, Stockholm, Sweden. (D) 5-HT transporter (SERT). HRRT PET image of [¹¹C]DASB brain distribution, from Center for Integrated Molecular Brain Imaging (Cimbi), Copenhagen, Denmark. (E) 5-HT_2A receptor. HRRT PET image of [¹⁸F]altanserin brain distribution, from Center for Integrated Molecular Brain Imaging (Cimbi),Copenhagen, Denmark. (F) 5-HT₄ receptor. HRRTPET image of [¹¹C]SB207145 brain distribution, from Center for Integrated Molecular Brain Imaging (Cimbi),Copenhagen, Denmark.