Preclinical validation of [18F]2FNQ1P as a specific PET radiotracer of 5-HT6 receptors in rat, pig, non-human primate and human brain tissue

Positron Emission Tomography (PET) Imaging Tracers for Serotonin Receptors

“…Pretreatment with cold 2FNQ1P or SB258585 led to a remarkable reduction of radioactive levels in the striatum, suggesting its good binding specificity. The specific binding to 5-HT 6 receptors was further confirmed by in vitro ARG and saturation binding assays with rat, pig, NHP, and human brain tissues . More recently, a series of indole compounds ( O -[ 11 C] 148 – 151 and N -[ 11 C] 148 – 151 , Figure ) with a methyl piperazinyl group were developed as 5-HT 6 PET ligands by 11 C-labeling through O - or N - 11 C-methylation .…”

“…The specific binding to 5-HT 6 receptors was further confirmed by in vitro ARG and saturation binding assays with rat, pig, NHP, and human brain tissues. 428 21) with a methyl piperazinyl group were developed as 5-HT 6 PET ligands by 11 C-labeling through O-or N-11 C-methylation. 429 These compounds had high affinities to 5-HT 6 Rs with the K i values of 2.0, 4.3, 1.6, and 5.0 nM.…”

Radiotracers for the Central Serotoninergic System

“…The distribution of [ 18 F]2FNQ1P in 5-HT 6 R-dense regions (i.e., the cortex and striatum) was assessed by semiquantitative autoradiography in rat brains. Furthermore, the addition of SB2258585 (a specific 5-HT 6 R antagonist) displaced the binding of [ 18 F]2FNQ1P in a concentration-dependent manner, confirming its excellent specificity for 5-HT 6 R [ 233 ]. The cerebral distribution of [ 18 F]2FNQ1P was then studied in vivo in various animal models, from rodents to nonhuman primates.…”

“…By contrast, in vivo PET imaging with [ 18 F]2FNQ1P in feline and primate models showed high uptake and distribution in the striatal regions particularly rich in 5-HT 6 R, suggesting that [ 18 F]2FNQ1P could be a suitable 5-HT 6 R PET tracer for quantification of the brain 5-HT 6 R in primates. A recent in vitro study demonstrates a decrease in the caudate nucleus 5-HT 6 R density with [ 18 F]2FNQ1P in human brain tissue from patients with different stages of Alzheimer’s disease [ 233 ]. Future in vivo exploration should be carried out to establish the relevance of [ 18 F]2FNQ1P to confirm an early decline in 5-HT 6 R expression during the progression of the disease.…”

Novel PET Biomarkers to Disentangle Molecular Pathways across Age-Related Neurodegenerative Diseases

“…( 18 F)MPPF PET studies showing reduced levels of serotonin type 1A (5-HT 1A ) receptors in the hippocampus of AD patients [247]. The development of PET tracers targeting the 5-HT6 receptor, such as ( 18 F)2FNQ1P [248,249], could play an important role to further explore the relationship of this serotonin receptor subtype with dementia. In FTD, the loss of 5-HT 2A receptors, measured using ( 11 C)MDL100907 PET, has been reported to underlie behavior diseases [250].…”