Design, synthesis, radiolabeling and in vivo evaluation of potential positron emission tomography (PET) radioligands for brain imaging of the 5-HT7 receptor

Lacivita, Enza; Niso, Mauro; Hansen, Hanne D.; Pilato, Pantaleo Di; Herth, Matthias M.; Lehel, Szabolcs; Ettrup, Anders; Montenegro, Lisa M.; Perrone, Roberto; Berardi, Francesco; Colabufo, Nicola Antonio; Leopoldo, Marcello; Knudsen, Gitte M.

doi:10.1016/j.bmc.2014.01.016

Cited by 22 publications

(19 citation statements)

References 43 publications

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“…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%

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: Methodsmentioning

confidence: 99%

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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“…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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“…We and others have investigated a number of ligands from different compound classes for the purpose of developing a 5‐HT 7 R PET radioligand . Of these, [ 11 C]Cimbi‐717 displayed the most promising results for selective 5‐HT 7 R PET imaging in pigs .…”

Section: Introductionmentioning

confidence: 99%

“…8 We and others have investigated a number of ligands from different compound classes for the purpose of developing a 5-HT 7 R PET radioligand. 5,[9][10][11][12][13][14] Of these, [ 11 C] Cimbi-717 displayed the most promising results for selective 5-HT 7 R PET imaging in pigs. 5 A series of 18 F-labelled compounds have been developed using SB-269970 as lead compound [15][16][17] because of its high affinity (K D = 1.3nM) and high selectivity for the 5-HT 7 R. 18 One promising analogue of SB-269970 is [ 18 F]2FP3 (K D = 8.4nM, human recombinant receptors in Chinese hamster ovary [CHO] cells), which displayed promising results when evaluated in cats.…”

Section: Introductionmentioning

confidence: 99%

Evaluation of [¹⁸F]2FP3 in pigs and non‐human primates

Hansen

Constantinescu

Barret

et al. 2018

Labelled Comp Radiopharmac

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So far, no suitable 5‐HT7R radioligand exists for clinical positron emission tomography (PET) imaging. [18F]2FP3 was first tested in vivo in cats, and the results were promising for further evaluations. Here, we evaluate the radioligand in pigs and non‐human primates (NHPs). Furthermore, we investigate species differences in 5‐HT7R binding with [3H]SB‐269970 autoradiography in post‐mortem pig, NHP, and human brain tissue. Specific binding of [18F]2FP3 was investigated by intravenous administration of the 5‐HT7R specific antagonist SB‐269970. [3H]SB‐269970 autoradiography was performed as previously described. [18F]2FP3 was synthesized in an overall yield of 35% to 45%. High brain uptake of the tracer was found in both pigs and NHPs; however, pretreatment with SB‐269970 only resulted in decreased binding of 20% in the thalamus, a 5‐HT7R–rich region. Autoradiography on post‐mortem pig, NHP, and human tissues revealed that specific binding of [3H]SB‐269970 was comparable in the thalamus of pig and NHP. Despite the high uptake of [18F]2FP3 in both species, the binding could only be blocked to a limited degree with the 5‐HT7R antagonists. We speculate that the affinity of the radioligand is too low for imaging the 5‐HT7Rs in vivo and that part of the PET signal arises from targets other than the 5‐HT7R.

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Design, synthesis, radiolabeling and in vivo evaluation of potential positron emission tomography (PET) radioligands for brain imaging of the 5-HT7 receptor

Cited by 22 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

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

Evaluation of [¹⁸F]2FP3 in pigs and non‐human primates

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Design, synthesis, radiolabeling and in vivo evaluation of potential positron emission tomography (PET) radioligands for brain imaging of the 5-HT7 receptor

Cited by 22 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

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

Evaluation of [18F]2FP3 in pigs and non‐human primates

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

Evaluation of [¹⁸F]2FP3 in pigs and non‐human primates