Synthesis and In Vitro Evaluation of Oxindole Derivatives as Potential Radioligands for 5-HT<sub>7</sub> Receptor Imaging with PET

Herth, Matthias M.; Volk, Balázs; Pallagi, Katalin; Bech, Lasse Kofoed; Antoni, Ferenc András; Knudsen, Gitte M.; Kristensen, Jesper L.

doi:10.1021/cn3001137

Cited by 26 publications

(29 citation statements)

References 39 publications

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“…Since the displaceable PET signal consists of density multiplied by affinity, a high B max and high K d will give a large PET signal compared to the corresponding signal from a relatively low abundance receptor. Receptor distribution (B max ) of colocalized targets 5-HT 1A and 5-HT 7 in thalamus are reported as 4.16 and 12 fmol/mg of tissue respectively (49). Therefore, corresponding ratios of 5-HT 7 to 5-HT 1A receptor in thalamus is 2.88.…”

Section: Discussionmentioning

confidence: 99%

Synthesis and in vivo evaluation of [18F]2-(4-(4-(2-(2-fluoroethoxy)phenyl)piperazin-1-yl)butyl)-4-methyl-1,2,4-triazine-3,5(2H,4H)-dione ([18F]FECUMI-101) as an imaging probe for 5-HT1A receptor agonist in nonhuman primates

Majo

Milak

Prabhakaran

et al. 2013

Bioorganic & Medicinal Chemistry

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The 5-HT1AR partial agonist PET radiotracer, [11C]CUMI-101, has advantages over an antagonist radiotracer as it binds preferentially to the high affinity state of the receptor and thereby provides more functionally meaningful information. The major drawback of C-11 tracers is the lack of cyclotron facility in many health care centers thereby limiting widespread clinical or research use. We identified the fluoroethyl derivative, 2-(4-(4-(2-(2-fluoroethoxy)phenyl)piperazin-1-yl)butyl)-4-methyl-1,2,4-triazine-3,5(2H,4H)dione (FECUMI-101) (Ki = 0.1 nM; Emax = 77%; EC50 = 0.65 nM) as a partial agonist 5-HT1AR ligand of the parent ligand CUMI-101. FECUMI-101 is radiolabeled with F-18 by O-fluoroethylation of the corresponding desmethyl analogue (1) with [18F]fluoroethyltosylate in DMSO in the presence of 1.6 equiv. of K2CO3 in 45 ± 5% yield (EOS). PET shows [18F]FECUMI-101 binds specifically to 5-HT1AR enriched brain regions of baboon. The specificity of [18F]FECUMI-101 binding to 5-HT1AR was confirmed by challenge studies with the known 5-HT1AR ligand WAY100,635. These findings indicate that [18F]FECUMI-101 can be a viable agonist ligand for the in vivo quantification of high affinity 5-HT1AR with PET.

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Section: Discussionmentioning

confidence: 99%

Synthesis and in vivo evaluation of [18F]2-(4-(4-(2-(2-fluoroethoxy)phenyl)piperazin-1-yl)butyl)-4-methyl-1,2,4-triazine-3,5(2H,4H)-dione ([18F]FECUMI-101) as an imaging probe for 5-HT1A receptor agonist in nonhuman primates

Majo

Milak

Prabhakaran

et al. 2013

Bioorganic & Medicinal Chemistry

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“…The precursors and reference compounds were synthesized as racemates as previously described (12,13).…”

Section: Organic Synthesismentioning

confidence: 99%

“…Cimbi-712 is 2,191-fold selective for 5-HT 7 R over 5-HT 1A R (K i for the 5-HT 1A R is 2,410 nM), whereas Cimbi-717 is 130-fold selective (K i for the 5-HT 1A R is 261 nM). From the outcome of the affinity testing on a range of receptors, Cimbi-712 displayed slightly higher selectivity for 5-HT 7 R than did Cimbi-717 (12).…”

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confidence: 98%

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

et al. 2014

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The serotonin (5-hydroxytryptamine [5-ΗΤ]) 7 receptor (5-HT 7 R) is the most recently discovered 5-HT receptor, and its physiologic and possible pathophysiologic roles are not fully elucidated. So far, no suitable 5-HT 7 R PET radioligand is available, thus limiting the investigation of this receptor in the living brain. Here, we present the radiosynthesis and in vivo evaluation of piperazine-1-yl]butyl}p-1,3-dihydro-2H-indol-2-one) and piperazine-1-yl]butyl}-1,3-dihydro-2H-indol-2-one) as selective 5-HT 7 R PET radioligands in the pig brain. The 5-HT 7 R distribution in the postmortem pig brain is also assessed. Methods: In vitro autoradiography with the 5-HT 7 R selective radioligand 3 H-labeled (R)-3-(2-(2-(4-methylpiperidin-1-yl) ethyl)pyrrolidine-1-sulfonyl)phenol (SB-269970) was performed on pig brain sections to establish the 5-HT 7 R binding distribution. Radiolabeling of 5-HT 7 R selective compounds was performed in an automated synthesis module in which we conducted either palladiummediated cross coupling ( 11 C-Cimbi-712) or conventional O-methylation ( 11 C-Cimbi-717) using 11 C-MeI and 11 C-MeOTf, respectively. After intravenous injection of the radioligands in Danish Landrace pigs, the in vivo brain distribution of the ligands was studied. Specific binding of 11 C-Cimbi-712 and 11 C-Cimbi717 to 5-HT 7 R was investigated by intravenous administration of SB-269970 before a second PET scan. Results: High 5-HT 7 R density was found in the thalamus and cortical regions of the pig brain by autoradiography. The radiosynthesis of both radioligands succeeded after optimization efforts (radiochemical yield, ∼20%-30% at the end of synthesis). Timeactivity curves of 11 C-Cimbi-712 and 11 C-Cimbi-717 showed high brain uptake and distribution according to 5-HT 7 R distribution, but the tracer kinetics of 11 C-Cimbi-717 were faster than 11 C-Cimbi-712. Both radioligands were specific for 5-HT 7 R, as binding could be blocked by pretreatment with SB-269970 for 11 C-Cimbi-717 in a dose-dependent fashion. For 11 C-Cimbi-717, nondisplaceable binding potentials of 6.4 ± 1.2 (n 5 6) were calculated in the thalamus. Conclusion: Both 11 C-Cimbi-712 and 11 C-Cimbi-717 generated a specific binding in accordance with 5-HT 7 R distribution and are potential PET radioligands for 5-HT 7 R. 11 C-Cimbi-717 is the better candidate because of the more reversible tracer kinetics, and this radioligand showed a dose-dependent decline in cerebral binding after receptor blockade. Thus, 11 C-Cimbi-717 is currently the most promising radioligand for investigation of 5-HT 7 R binding in the living human brain. The serotonergic system plays a key modulatory role in the brain and is a target for many drug treatments for brain disorders either through reuptake blockade or interactions with one or more of the 14 subtypes of 5-hydroxytryptamine (5-HT) receptors. Our knowledge about the behavior of the 5-HT system in vivo is still scattered, and most of the understanding is derived from animal models. However, the use of imaging techniques such...

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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%

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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Synthesis and In Vitro Evaluation of Oxindole Derivatives as Potential Radioligands for 5-HT₇ Receptor Imaging with PET

Cited by 26 publications

References 39 publications

Synthesis and in vivo evaluation of [18F]2-(4-(4-(2-(2-fluoroethoxy)phenyl)piperazin-1-yl)butyl)-4-methyl-1,2,4-triazine-3,5(2H,4H)-dione ([18F]FECUMI-101) as an imaging probe for 5-HT1A receptor agonist in nonhuman primates

Synthesis and in vivo evaluation of [18F]2-(4-(4-(2-(2-fluoroethoxy)phenyl)piperazin-1-yl)butyl)-4-methyl-1,2,4-triazine-3,5(2H,4H)-dione ([18F]FECUMI-101) as an imaging probe for 5-HT1A receptor agonist in nonhuman primates

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

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Synthesis and In Vitro Evaluation of Oxindole Derivatives as Potential Radioligands for 5-HT7 Receptor Imaging with PET

Cited by 26 publications

References 39 publications

Synthesis and in vivo evaluation of [18F]2-(4-(4-(2-(2-fluoroethoxy)phenyl)piperazin-1-yl)butyl)-4-methyl-1,2,4-triazine-3,5(2H,4H)-dione ([18F]FECUMI-101) as an imaging probe for 5-HT1A receptor agonist in nonhuman primates

Synthesis and in vivo evaluation of [18F]2-(4-(4-(2-(2-fluoroethoxy)phenyl)piperazin-1-yl)butyl)-4-methyl-1,2,4-triazine-3,5(2H,4H)-dione ([18F]FECUMI-101) as an imaging probe for 5-HT1A receptor agonist in nonhuman primates

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

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Synthesis and In Vitro Evaluation of Oxindole Derivatives as Potential Radioligands for 5-HT₇ Receptor Imaging with PET

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