Radiosynthesis and In Vivo Evaluation of Novel Radioligands for PET Imaging of Cerebral 5-HT<sub>7</sub> Receptors

A series of 5-aryl-1-alkylimidazole derivatives was synthesized using the van Leusen multicomponent reaction. The chemotype is the first example of low-basicity scaffolds exhibiting high affinity for 5-HT 7 receptor together with agonist function. The chosen lead compounds 3-(1-ethyl-1H-imidazol-5-yl)-5-iodo-1H-indole (AGH-107, 1o, K i 5-HT7 = 6 nM, EC 50 = 19 nM, 176-fold selectivity over 5-HT 1A R) and 1e (5-methoxy analogue, K i 5-HT7 = 30 nM, EC 50 = 60 nM) exhibited high selectivity over related CNS targets, high metabolic stability and low toxicity in HEK-293 and HepG2 cell cultures. A rapid absorption to the blood, high blood-brain barrier permeation and a very high peak concentration in the brain (C max = 2723 ng/g) were found for 1o after i.p. (5 mg/kg) administration in mice. The compound was found active in novel object recognition test in mice, at 0.5, 1 and 5 mg/kg. Docking to 5-HT 7 R homology models indicated a plausible binding mode which explain the unusually high selectivity over the related CNS targets. Halogen bond formation between the most potent derivatives and the receptor is consistent with both the docking results and SAR. 5-Chlorine, bromine and iodine substitution resulted in a 13, 27 and 89-fold increase in binding affinities, respectively, and in enhanced 5-HT 1A R selectivity.Within the serotonergic system, 5-HT 7 , the last identified serotonin receptor, is one of the most valuable drug targets 1 . Discovered independently by three laboratories in 1993 2-4 , 5-HT 7 R was thought to function by being coupled to G s to stimulate intracellular production of cAMP, but it was later found to also be coupled to G 12 which is an alternative signal transduction pathway 5 . 5-HT 7 R is expressed in the central nervous system (thalamus, hypothalamus, hippocampus and cortex) as well as peripherally (pancreas, spleen, coronary artery, ileum and intestine) [3][4][5][6] . Experiments using animal models have shown that the receptor is involved in many physiological processes, i.e. the regulation of body temperature 7 , smooth muscle relaxation of cerebral arteries 8 , circadian rhythm, learning and memory 9-13 , as well as pathophysiological processes such as mood disorders, anxiety 14 , inflammatory processes in the CNS 15 , schizophrenia 16 and pain 17,18 . 5-HT 7 R antagonists have been proposed as potential drugs targeting depression 19,20 . There have been less conclusive reports on potential anxiolytic 21,22 , analgesic 17 and antipsychotic properties of the receptor ligands 23,24 . It was established that 5-HT 7 R blockade can induce promnesic effects indicating the possibility of developing atypical procognitive antidepressants 25 .There are several 5-HT 7 R agonists available to serve as molecular probes. These include small, low-weight molecules, e.g. AS-19 26 , RA-7 7 , 5-carboxyamidotryptamine (5-CT), 5-methoxytryptamine, 8-OH-DPAT 27 , and lysergic acid derivatives 28 and long-chain diphenylpiperazines (LP-12, LP-44, LP-211) developed by . None of these compounds qualify as perfect...

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“…5-HT 7 receptor is yet to be PET imaged in humans 53 . No suitable 5-HT 7 R agonist radioligand candidates were reported till date 54, 55 .…”

Section: Resultsmentioning

confidence: 99%

Low-basicity 5-HT7 Receptor Agonists Synthesized Using the van Leusen Multicomponent Protocol

Hogendorf

Kurczab

et al. 2017

Sci Rep

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“…11) and [ 11 C]CIMBI-717 (K i = 2.6 nM, Fig. 11), the two selective phenylpiperazinyl butyloxindole derivatives have been studied as 5-HT 7 R ligands in pigs [180] and the latter shows higher uptake and specific binding than [ 11 C]CIMBI-712. In summary, [ 18 F]2FP3 and [ 11 C]CIMBI-717 are the two PET ligands proven successful in vivo in cats and pigs, respectively.…”

Section: Introductionmentioning

confidence: 99%

PET Tracers for Serotonin Receptors and Their Applications

Js¹,

Mann

2015

CNSAMC

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Serotonin receptors (5-HTRs) are implicated in the pathophysiology of a variety of neuropsychiatric and neurodegenerative disorders and are also targets for drug therapy. In the CNS, most of these receptors are expressed in high abundance in specific brain regions reflecting their role in brain functions. Quantifying binding to 5-HTRs in vivo may permit assessment of physiologic and pathologic conditions, and monitoring disease progression, evaluating treatment response, and for investigating new treatment modalities. Positron emission tomography (PET) molecular imaging has the sensitivity to quantify binding of 5-HTRs in CNS disorders and to measure drug occupancy as part of a process of new drug development. Although research on PET imaging of 5-HTRs have been performed more than two decades, the successful radiotracers so far

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“…Several selective 5‐HT 7 R compounds have been developed, and some have been radiolabelled for use in radioligand binding assays and in vitro autoradiography studies. For example, [ 3 H]SB‐269970 has been used for in vitro experiments in rodent, pig, marmoset, and human brain tissue . In recent years, there has been a large effort to identify a radioligand for PET imaging.…”

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

“…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 . A series of 18 F‐labelled compounds have been developed using SB‐269970 as lead compound because of its high affinity ( K D = 1.3nM) and high selectivity for the 5‐HT 7 R .…”

Section: Introductionmentioning

confidence: 99%

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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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Radiosynthesis and In Vivo Evaluation of Novel Radioligands for PET Imaging of Cerebral 5-HT₇ Receptors

Cited by 34 publications

References 27 publications

Low-basicity 5-HT7 Receptor Agonists Synthesized Using the van Leusen Multicomponent Protocol

Low-basicity 5-HT7 Receptor Agonists Synthesized Using the van Leusen Multicomponent Protocol

PET Tracers for Serotonin Receptors and Their Applications

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

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Radiosynthesis and In Vivo Evaluation of Novel Radioligands for PET Imaging of Cerebral 5-HT7 Receptors

Cited by 34 publications

References 27 publications

Low-basicity 5-HT7 Receptor Agonists Synthesized Using the van Leusen Multicomponent Protocol

Low-basicity 5-HT7 Receptor Agonists Synthesized Using the van Leusen Multicomponent Protocol

PET Tracers for Serotonin Receptors and Their Applications

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

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Radiosynthesis and In Vivo Evaluation of Novel Radioligands for PET Imaging of Cerebral 5-HT₇ Receptors

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