Radiosynthesis and preclinical evaluation of [¹¹C]Cimbi‐701 – Towards the imaging of cerebral 5‐HT₇ receptors

Abstract

The serotonin 7 (5-HT 7 ) receptor is suggested to be involved in a broad variety of CNS disorders, but very few in vivo tools exist to study this important target.Molecular imaging with positron emission tomography (PET) would enable an in vivo characterization of the 5-HT 7 receptor. However, no clinical PET radiotracer exists for this receptor, and thus we aimed to develop such a tracer. In this study, we present the preclinical evaluation of [ 11 C]Cimbi-701. Cimbi-701 was synthesized in a one-step procedure starting from SB-269970. Its selectivity profile was determined using an academic screening platform (NIMH Psychoactive Drug Screening Program). Successful radiolabeling of [ 11 C]Cimbi-701 and subsequent in vivo evaluation was conducted in rats, pigs and baboon. In vivo specificity was investigated by 5-HT 7 and σ receptor blocking studies. P-gp efflux transporter dependency was investigated using elacridar.[ 11 C]Cimbi-701 could successfully be synthesized. Selectivity profiling revealed high affinity for the 5-HT 7 (K i = 18 nM), σ-1 (K i = 9.2 nM) and σ-2 (K i = 1.6 nM) receptors. In rats, [ 11 C]Cimbi-701 acted as a strong P-gp substrate. After P-gp inhibition, rat brain uptake could specifically be blocked by 5-HT 7 and σ receptor ligands. In pig, high brain uptake and specific 5-HT 7 and σreceptor binding was found for [ 11 C]Cimbi-701 without P-gp inhibition.Finally, low brain uptake was found in baboons. Both the specific σ-receptor binding and the low brain uptake of [ 11 C]Cimbi-701 displayed in baboon discouraged further translation to humans. Instead, we suggest exploration of this structural class as results indicate that selective 5-HT 7 receptor imaging might be possible when more selective non-P-gp substrates are identified.

Blocking of efflux transporters in rats improves translational validation of brain radioligands

“…Among tracers targeting 5-HT 7 receptors, we investigated [ 11 C]Cimbi-717, [ 11 C]Cimbi-701 and [ 11 C]BA-10 [ 16 , 17 , 27 ]. At baseline, all tracers showed low AUC values between 30 and 43 min × g/mL in the 5-HT 7 receptor-rich thalamus (Fig.…”

“…Evaluation of [ 18 F]MH.MZ, [ 18 F]Altanserin, [ 11 C]Pimavanserin, [ 11 C]Cimbi-36, [ 11 C]Cimbi-717 and [ 11 C]Cimbi-701 in pigs was reported previously [ 15 , 19 , 27 , 28 ]. Time–activity curves for [ 11 C]BA-10 and [ 18 F]Fallypride in pig brain are presented in Additional file 1 : Figs.…”

Positron Emission Tomography (PET) Imaging Tracers for Serotonin Receptors

“…These results limited the usefulness of [ 18 F] 165 as a potential PET ligand for 5-HT 7 receptors. An additional close analog of SB266970, [ 11 C]­Cimbi-701 ([ 11 C] 166 , Figure ), was developed as a radiotracer for 5-HT 7 receptors by 11 C-labeling of SB266970 with [ 11 C]­methyl triflate . Cimbi-701 shows moderate affinity to 5-HT 7 receptors ( K i = 18 nM), but it binds to σ 1 and σ 2 receptors with high affinities of 9.2 and 1.6 nM ( K i value), respectively.…”

Radiotracers for the Central Serotoninergic System

“…Still in the N -sulfopyrrolidine series, two radioligands were synthesized and tested by Herth et al: [ 18 F]ENL30 [ 247 ] and [ 11 C]CIMBI-701 [ 248 ] ( Figure 20 ). These compounds exhibited mixed labeling of the 5-HT 7 R and σ-receptors and added to a moderate signal in the brain (probably linked to the mechanisms of efflux (P-gp substrate)), thus limiting their use in humans.…”