Synthesis, radiolabeling and in vivo evaluation of [11C](R)-1-[4-[2-(4-methoxyphenyl)phenyl]piperazin-1-yl]-3-(2-pyrazinyloxy)-2-propanol, a potential PET radioligand for the 5-HT7 receptor

Hansen, Hanne D.; Lacivita, Enza; Pilato, Pantaleo Di; Herth, Matthias M.; Lehel, Szabolcs; Ettrup, Anders; Andersen, Valdemar L.; Dyssegaard, Agnete; Giorgio, Paola De; Perrone, Roberto; Berardi, Francesco; Colabufo, Nicola Antonio; Niso, Mauro; Knudsen, Gitte M.; Leopoldo, Marcello

doi:10.1016/j.ejmech.2014.03.066

Cited by 26 publications

(21 citation statements)

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“…Consistently, in vivo results recently published (Hansen et al, 2014) show that BA-10 is not significantly transported by P-glycoprotein and reaches high brain concentrations following intravenous injection. Therefore, the pharmacokinetic properties of BA-10 are promising and deserve to be further investigated.…”

Section: Discussionsupporting

confidence: 88%

“…BA/AB ratios of the test compounds are listed in Table 1: all the compounds tested appeared to be weak substrates, thus should only weakly interact with P-gp. In line with this, a recent positron emission tomography study performed with [ 11 C]BA-10 clearly showed in vivo that BA-10 is not a P-gp substrate, being able to massively accumulate into the brain (Hansen et al, 2014), thus is likely to act on the central nervous system following systemic administration.…”

Section: Resultsmentioning

confidence: 68%

“…The synthesis of the following 5-HT 7 receptor ligands was accomplished as previously reported: N -(4-cyanophenylmethyl)-4-(2-diphenyl)-1-piperazinehexanamide, LP-211 (Leopoldo et al, 2008), ( R )-1-[4-[2-(4-methoxyphenyl)phenyl]piperazin-1-yl]-3-(2-pyrazinyloxy)-2-propanol, BA-10 (Hansen et al, 2014), N-(2-fluoropyridin-5-ylmethyl)-4-[2-(4-methoxy)phenyl]-1-pip erazinehexanamide, PF-62 (Lacivita et al, 2014), 1-(2-biphenyl)piperazine, RA-7 (Bantle, 1996), 1-[2-(4-methoxyphenyl)phenyl]piperazine, PM-20 (Lacivita et al, 2012). N -(4-cyanophenylmethyl)-3-[4-[2-(4-methoxyphenyl)phenyl]pipe-razin-1-yl]ethoxy]propanamide, MM-1, and N -(4-trifuoromethylphenylmethyl)-3-[4-[2-(4-methoxyphenyl)phenyl]pipe-razin-1-yl]ethoxy]propanamide, MM-2, were synthesized as depicted in Figure 1 (Scheme 1).…”

Section: Methodsmentioning

confidence: 99%

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Novel agonists for serotonin 5-HT7 receptors reverse metabotropic glutamate receptor-mediated long-term depression in the hippocampus of wild-type and Fmr1 KO mice, a model of Fragile X Syndrome

Costa

Sardone

Lacivita

et al. 2015

Front. Behav. Neurosci.

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Serotonin 5-HT7 receptors are expressed in the hippocampus and modulate the excitability of hippocampal neurons. We have previously shown that 5-HT7 receptors modulate glutamate-mediated hippocampal synaptic transmission and long-term synaptic plasticity. In particular, we have shown that activation of 5-HT7 receptors reversed metabotropic glutamate receptor-mediated long-term depression (mGluR-LTD) in wild-type (wt) and in Fmr1 KO mice, a mouse model of Fragile X Syndrome in which mGluR-LTD is abnormally enhanced, suggesting that 5-HT7 receptor agonists might be envisaged as a novel therapeutic strategy for Fragile X Syndrome. In this perspective, we have characterized the basic in vitro pharmacokinetic properties of novel molecules with high binding affinity and selectivity for 5-HT7 receptors and we have tested their effects on synaptic plasticity using patch clamp on acute hippocampal slices. Here we show that LP-211, a high affinity selective agonist of 5-HT7 receptors, reverses mGluR-LTD in wt and Fmr1 KO mice, correcting a synaptic malfunction in the mouse model of Fragile X Syndrome. Among novel putative agonists of 5-HT7 receptors, the compound BA-10 displayed improved affinity and selectivity for 5-HT7 receptors and improved in vitro pharmacokinetic properties with respect to LP-211. BA-10 significantly reversed mGluR-LTD in the CA3-CA1 synapse in wt and Fmr1KO mice, indicating that BA-10 behaved as a highly effective agonist of 5-HT7 receptors and reduced exaggerated mGluR-LTD in a mouse model of Fragile X Syndrome. On the other side, the compounds RA-7 and PM-20, respectively arising from in vivo metabolism of LP-211 and BA-10, had no effect on mGluR-LTD thus did not behave as agonists of 5-HT7 receptors in our conditions. The present results provide information about the structure-activity relationship of novel 5-HT7 receptor agonists and indicate that LP-211 and BA-10 might be used as novel pharmacological tools for the therapy of Fragile X Syndrome.

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Section: Discussionsupporting

confidence: 88%

Section: Resultsmentioning

confidence: 68%

Section: Methodsmentioning

confidence: 99%

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Novel agonists for serotonin 5-HT7 receptors reverse metabotropic glutamate receptor-mediated long-term depression in the hippocampus of wild-type and Fmr1 KO mice, a model of Fragile X Syndrome

Costa

Sardone

Lacivita

et al. 2015

Front. Behav. Neurosci.

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“…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.…”

Section: Resultsmentioning

confidence: 99%

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

et al. 2020

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Background Positron emission tomography (PET) is a molecular imaging technique that can be used to investigate the in vivo pharmacology of drugs. Initial preclinical evaluation of PET tracers is often conducted in rodents due to the accessibility of disease models as well as economic considerations. Compared to larger species, rodents display a higher expression and/or activity of efflux transporters such as the P-glycoprotein (P-gp). Low brain uptake could, therefore, be species-specific and uptake in rodents not be predictive for that in humans. We hypothesized that a better prediction from rodent data could be achieved when a tracer is evaluated under P-gp inhibition. Consequently, we compared the performance of eight neuroreceptor tracers in rats with and without P-gp inhibition including a specific binding blockade. This data set was then used to predict the binding of these eight tracers in pigs. Methods PET tracers targeting serotonin 5-HT2A receptors ([18F]MH.MZ, [18F]Altanserin, [11C]Cimbi-36, [11C]Pimavanserin), serotonin 5-HT7 receptors ([11C]Cimbi-701, [11C]Cimbi-717 and [11C]BA-10) and dopamine D2/3 receptors ([18F]Fallypride) were used in the study. The brain uptake and target-specific binding of these PET radiotracers were evaluated in rats with and without inhibition of P-gp. Rat data were subsequently compared to the results obtained in pigs. Results Without P-gp inhibition, the amount of target-specific binding in the rat brain was sufficient to justify further translation for three out of eight evaluated tracers. With P-gp inhibition, results for five out of eight tracers justified further translation. The performance in pigs could correctly be predicted for six out of eight tracers when rat data obtained under P-gp inhibition were used, compared to four out of eight tracers without P-gp inhibition. Conclusions P-gp strongly affects the uptake of PET tracers in rodents, but false prediction outcomes can be reduced by evaluating a tracer under P-gp inhibition.

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“…A PET radiotracer for the 5‐HT 7 receptor would aid in exploring the role of this receptor in healthy and diseased brains. To our knowledge, no clinical PET tracer exists for the 5‐HT 7 receptor even though several attempts have been made . Figure 1 displays some key structures that have been used over the years.…”

Section: Introductionmentioning

confidence: 99%

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

'Estrade

Shalgunov

Edgar

et al. 2020

Labelled Comp Radiopharmac

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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.

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Synthesis, radiolabeling and in vivo evaluation of [11C](R)-1-[4-[2-(4-methoxyphenyl)phenyl]piperazin-1-yl]-3-(2-pyrazinyloxy)-2-propanol, a potential PET radioligand for the 5-HT7 receptor

Cited by 26 publications

References 43 publications

Novel agonists for serotonin 5-HT7 receptors reverse metabotropic glutamate receptor-mediated long-term depression in the hippocampus of wild-type and Fmr1 KO mice, a model of Fragile X Syndrome

Novel agonists for serotonin 5-HT7 receptors reverse metabotropic glutamate receptor-mediated long-term depression in the hippocampus of wild-type and Fmr1 KO mice, a model of Fragile X Syndrome

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

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

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Synthesis, radiolabeling and in vivo evaluation of [11C](R)-1-[4-[2-(4-methoxyphenyl)phenyl]piperazin-1-yl]-3-(2-pyrazinyloxy)-2-propanol, a potential PET radioligand for the 5-HT7 receptor

Cited by 26 publications

References 43 publications

Novel agonists for serotonin 5-HT7 receptors reverse metabotropic glutamate receptor-mediated long-term depression in the hippocampus of wild-type and Fmr1 KO mice, a model of Fragile X Syndrome

Novel agonists for serotonin 5-HT7 receptors reverse metabotropic glutamate receptor-mediated long-term depression in the hippocampus of wild-type and Fmr1 KO mice, a model of Fragile X Syndrome

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

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

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Product

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About

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