Evaluation of the Novel 5-HT4 Receptor PET Ligand [11C]SB207145 in the Göttingen Minipig

This study investigates 5-hydroxytryptamine 4 (5-HT4) receptor binding in the minipig brain with positron emission tomography (PET), tissue homogenate-binding assays, and autoradiography in vitro. The cerebral uptake and binding of the novel 5-HT4 receptor radioligand [11C]SB207145 in vivo was modelled and the outcome compared with postmortem receptor binding. Different models for quantification of [11C]SB207145 binding were evaluated: One-tissue and two-tissue compartment kinetic modelling, Logan arterial input, and three different reference tissue models. We report that the pig autoradiographic 5-HT4 receptor distribution resembles the human 5-HT4 receptor distribution with the highest binding in the striatum and no detectable binding in the cerebellum. We found that in the minipig brain [11C]SB207145 follows one-tissue compartment kinetics, and the simplified reference tissue model provides stable and precise estimates of the binding potential in all regions. The binding potentials calculated for striatum, midbrain, and cortex from the PET data were highly correlated with 5-HT4 receptor concentrations determined in brain homogenates from the same regions, except for hippocampus where PET-measurements significantly underestimate the 5-HT4 receptor binding, probably because of partial volume effects. This study validates the use of [11C]SB207145 as a promising PET radioligand for in vivo brain imaging of the 5-HT4 receptor in humans.

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Synthesis and preclinical evaluation of [11C]MTP38 as a novel PET ligand for phosphodiesterase 7 in the brain

10.1101/2020.10.29.354696 ◽

2020 ◽

Author(s):

Naoyuki Obokata ◽

Chie Seki ◽

Takeshi Hirata ◽

Jun Maeda ◽

Hideki Ishii ◽

...

Keyword(s):

Arterial Input Function ◽

Inflammatory Diseases ◽

Input Function ◽

Binding Potential ◽

Dependent Manner ◽

Reference Tissue ◽

Molar Activity ◽

The Brain

AbstractPurposePhosphodiesterase (PDE) 7 is a potential therapeutic target for neurological and inflammatory diseases, although in-vivo visualization of PDE7 has not been successful. In this study, we aimed to develop [11C]MTP38 as a novel positron emission tomography (PET) ligand for PDE7.Methods[11C]MTP38 was radiosynthesized by 11C-cyanation of a bromo precursor with [11C]HCN. PET scans of rat and rhesus monkey brains and in-vitro autoradiography of brain sections derived from these species were conducted with [11C]MTP38. In monkeys, dynamic PET data were analyzed with an arterial input function to calculate the total distribution volume (VT). The non-displaceable binding potential (BPND) in the striatum was also determined by a reference tissue model with cerebellar reference. Finally, striatal occupancy of PDE7 by an inhibitor was calculated in monkeys according to changes in BPND.Results[11C]MTP38 was synthesized with radiochemical purity ≥ 99.4% and molar activity of 38.6 ± 12.6 GBq/μmol. Autoradiography revealed high radioactivity in the striatum and its reduction by non-radiolabeled ligands, in contrast with unaltered autoradiographic signals in other regions. In-vivo PET after radioligand injection to rats and monkeys demonstrated that radioactivity was rapidly distributed to the brain and intensely accumulated in the striatum relative to the cerebellum. Correspondingly, estimated VT values in the monkey striatum and cerebellum were 3.59 and 2.69 mL/cm3, respectively. The cerebellar VT value was unchanged by pretreatment with unlabeled MTP38. Striatal BPND was reduced in a dose-dependent manner after pretreatment with MTP-X, a PDE7 inhibitor. Relationships between PDE7 occupancy by MTP-X and plasma MTP-X concentration could be described by Hill’s sigmoidal function.ConclusionWe have provided the first successful preclinical demonstration of in-vivo PDE7 imaging with a specific PET radioligand. [11C]MTP38 is a feasible radioligand for evaluating PDE7 in the brain and is currently being applied to a first-in-human PET study.

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Loss of D2 Receptor Binding with Age in Rhesus Monkeys: Importance of Correction for Differences in Striatal Size

Journal of Cerebral Blood Flow & Metabolism ◽

10.1097/00004647-199902000-00013 ◽

1999 ◽

Vol 19 (2) ◽

pp. 218-229 ◽

Cited By ~ 48

Author(s):

Evan D. Morris ◽

Svetlana I. Chefer ◽

Mark A. Lane ◽

Raymond F. Muzic ◽

Dean F. Wong ◽

...

Keyword(s):

Receptor Binding ◽

Rhesus Monkeys ◽

Structural Changes ◽

D2 Receptor ◽

Binding Potential ◽

Age Related ◽

Positron Emission ◽

Dopamine Receptor Binding

The relation between striatal dopamine D2 receptor binding and aging was investigated in rhesus monkeys with PET. Monkeys (n = 18, 39 to 360 months of age) were scanned with 11C-raclopride; binding potential in the striatum was estimated graphically. Because our magnetic resonance imaging analysis revealed a concomitant relation between size of striatum and age, the dynamic positron emission tomography (PET) data were corrected for possible partial volume (PV) artifacts before parameter estimation. The age-related decline in binding potential was 1% per year and was smaller than the apparent effect if the age-related change in size was ignored. This is the first in vivo demonstration of a decline in dopamine receptor binding in nonhuman primates. The rate of decline in binding potential is consistent with in vitro findings in monkeys but smaller than what has been measured previously in humans using PET. Previous PET studies in humans, however, have not corrected for PV error, although a decline in striatal size with age has been demonstrated. The results of this study suggest that PV correction must be applied to PET data to accurately detect small changes in receptor binding that may occur in parallel with structural changes in the brain.

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Direct in vitro and in vivo demonstration of muscarinic receptor binding by the novel radioligand, [3H]5-hydroxymethyltolterodine, in the bladder and other tissues of rats

Journal of Pharmacological Sciences ◽

10.1016/j.jphs.2019.12.004 ◽

2020 ◽

Vol 142 (3) ◽

pp. 127-130

Author(s):

Shizuo Yamada ◽

Shiori Kuraoka ◽

Yoshihiko Ito ◽

Satomi Kagota ◽

Kazumasa Shinozuka ◽

...

Keyword(s):

Muscarinic Receptor ◽

Receptor Binding ◽

The Novel

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In vivo and in vitro Validation of Reference Tissue Models for the mGluR5 Ligand [11C]ABP688

Journal of Cerebral Blood Flow & Metabolism ◽

10.1038/jcbfm.2010.65 ◽

2010 ◽

Vol 30 (8) ◽

pp. 1538-1549 ◽

Cited By ~ 42

Author(s):

David Elmenhorst ◽

Luciano Minuzzi ◽

Antonio Aliaga ◽

Jared Rowley ◽

Gassan Massarweh ◽

...

Keyword(s):

Metabotropic Glutamate Receptor ◽

Primary Objective ◽

Binding Potential ◽

Reference Region ◽

Reference Tissue ◽

Caudate Putamen ◽

Average Decrease ◽

Arterial Blood

The primary objective of this study was to verify the suitability of reference tissue-based quantification methods of the metabotropic glutamate receptor type 5 (mGluR5) with [11C]ABP688. This study presents in vivo (Positron Emission Tomography (PET)) and in vitro (autoradiography) measurements of mGluR5 densities in the same rats and evaluates both noninvasive and blood-dependent pharmacokinetic models for the quantification of [11C]ABP688 binding. Eleven rats underwent [11C]ABP688 PET scans. In five animals, baseline scans were compared with blockade experiments with the antagonist 1,2-methyl-6-(phenylethynyl)-pyridine (MPEP), and arterial blood samples were drawn and corrected for metabolites. Afterward, saturation-binding autoradiography was performed. Blocking with MPEP resulted in an average decrease of the total distribution volume ( VT) between 43% and 58% (thalamus and caudate-putamen, respectively) but had no significant effect on cerebellar VT (mean reduction: −0.01%). Comparing binding potential ( BPND) based on the VT with noninvasively determined BPND revealed an average negative bias of 0.7% in the caudate-putamen and an average positive bias of 3.1% in the low-binding regions. Scan duration of 50 minutes is required. The cerebellum is a suitable reference region for the quantification of mGluR5 availability as measured with [11C]ABP688 PET in rats. Blood-based and reference region-based PET quantification shows a significant linear relationship to autoradiographic determinations.

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Neurokinin-3 Receptor Binding in Guinea Pig, Monkey, and Human Brain: In Vitro and in Vivo Imaging Using the Novel Radioligand, [18F]Lu AF10628

The International Journal of Neuropsychopharmacology ◽

10.1093/ijnp/pyw023 ◽

2016 ◽

Vol 19 (8) ◽

pp. pyw023

Author(s):

Katarina Varnäs ◽

Sjoerd J. Finnema ◽

Vladimir Stepanov ◽

Akihiro Takano ◽

Miklós Tóth ◽

...

Keyword(s):

Guinea Pig ◽

Human Brain ◽

Receptor Binding ◽

In Vivo Imaging ◽

The Novel ◽

Neurokinin 3 Receptor

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Synthesis and preclinical evaluation of [11C]MTP38 as a novel PET ligand for phosphodiesterase 7 in the brain

European Journal of Nuclear Medicine and Molecular Imaging ◽

10.1007/s00259-021-05269-4 ◽

2021 ◽

Author(s):

Naoyuki Obokata ◽

Chie Seki ◽

Takeshi Hirata ◽

Jun Maeda ◽

Hideki Ishii ◽

...

Keyword(s):

Arterial Input Function ◽

Inflammatory Diseases ◽

Input Function ◽

Binding Potential ◽

Dependent Manner ◽

Reference Tissue ◽

Molar Activity ◽

The Brain

Abstract Purpose Phosphodiesterase (PDE) 7 is a potential therapeutic target for neurological and inflammatory diseases, although in vivo visualization of PDE7 has not been successful. In this study, we aimed to develop [11C]MTP38 as a novel positron emission tomography (PET) ligand for PDE7. Methods [11C]MTP38 was radiosynthesized by 11C-cyanation of a bromo precursor with [11C]HCN. PET scans of rat and rhesus monkey brains and in vitro autoradiography of brain sections derived from these species were conducted with [11C]MTP38. In monkeys, dynamic PET data were analyzed with an arterial input function to calculate the total distribution volume (VT). The non-displaceable binding potential (BPND) in the striatum was also determined by a reference tissue model with cerebellar reference. Finally, striatal occupancy of PDE7 by an inhibitor was calculated in monkeys according to changes in BPND. Results [11C]MTP38 was synthesized with radiochemical purity ≥99.4% and molar activity of 38.6 ± 12.6 GBq/μmol. Autoradiography revealed high radioactivity in the striatum and its reduction by non-radiolabeled ligands, in contrast with unaltered autoradiographic signals in other regions. In vivo PET after radioligand injection to rats and monkeys demonstrated that radioactivity was rapidly distributed to the brain and intensely accumulated in the striatum relative to the cerebellum. Correspondingly, estimated VT values in the monkey striatum and cerebellum were 3.59 and 2.69 mL/cm3, respectively. The cerebellar VT value was unchanged by pretreatment with unlabeled MTP38. Striatal BPND was reduced in a dose-dependent manner after pretreatment with MTP-X, a PDE7 inhibitor. Relationships between PDE7 occupancy by MTP-X and plasma MTP-X concentration could be described by Hill’s sigmoidal function. Conclusion We have provided the first successful preclinical demonstration of in vivo PDE7 imaging with a specific PET radioligand. [11C]MTP38 is a feasible radioligand for evaluating PDE7 in the brain and is currently being applied to a first-in-human PET study.

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Characterization of the SARS-CoV-2 coronavirus X4-like accessory protein

Egyptian Journal of Medical Human Genetics ◽

10.1186/s43042-021-00160-1 ◽

2021 ◽

Vol 22 (1) ◽

Author(s):

Olanrewaju Ayodeji Durojaye ◽

Nkwachukwu Oziamara Okoro ◽

Arome Solomon Odiba

Keyword(s):

Rapid Development ◽

Protein A ◽

The Novel ◽

Quality Model ◽

A Value ◽

Model Protein ◽

Novel Coronavirus ◽

Global Threat

Abstract Background The novel coronavirus SARS-CoV-2 is currently a global threat to health and economies. Therapeutics and vaccines are in rapid development; however, none of these therapeutics are considered as absolute cure, and the potential to mutate makes it necessary to find therapeutics that target a highly conserved regions of the viral structure. Results In this study, we characterized an essential but poorly understood coronavirus accessory X4 protein, a core and stable component of the SARS-CoV family. Sequence analysis shows a conserved ~ 90% identity between the SARS-CoV-2 and previously characterized X4 protein in the database. QMEAN Z score of the model protein shows a value of around 0.5, within the acceptable range 0–1. A MolProbity score of 2.96 was obtained for the model protein and indicates a good quality model. The model has Ramachandran values of φ = − 57o and ψ = − 47o for α-helices and values of φ = − 130o and ψ = + 140o for twisted sheets. Conclusions The protein data obtained from this study provides robust information for further in vitro and in vivo experiment, targeted at devising therapeutics against the virus. Phylogenetic analysis further supports previous evidence that the SARS-CoV-2 is positioned with the SL-CoVZC45, BtRs-BetaCoV/YN2018B and the RS4231 Bat SARS-like corona viruses.

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In vitro and in vivo evaluation of a sustained-release once-a-day formulation of the novel antihypertensive drug MT-1207

Pharmaceutical Development and Technology ◽

10.1080/10837450.2021.1872087 ◽

2021 ◽

Vol 26 (3) ◽

pp. 349-361

Author(s):

Napoleon-Nikolaos Vrettos ◽

Peng Wang ◽

Yan Zhou ◽

Clive J. Roberts ◽

Jinyi Xu ◽

...

Keyword(s):

Sustained Release ◽

Antihypertensive Drug ◽

The Novel ◽

In Vivo Evaluation

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Overcoming multidrug-resistance in vitro and in vivo using the novel P-glycoprotein inhibitor 1416

Bioscience Reports ◽

10.1042/bsr20120020 ◽

2012 ◽

Vol 32 (6) ◽

pp. 559-566 ◽

Cited By ~ 19

Author(s):

Yan Xu ◽

Feng Zhi ◽

Guangming Xu ◽

Xiaolei Tang ◽

Sheng Lu ◽

...

Keyword(s):

Multidrug Resistance ◽

Cancer Chemotherapy ◽

Antitumour Activity ◽

Multidrug Resistant ◽

The Novel ◽

Mice Model ◽

P Glycoprotein ◽

Channel Currents

MDR (multidrug-resistance) represents a major obstacle to successful cancer chemotherapy and is usually accomplished by overexpression of P-gp (P-glycoprotein). Much effort has been devoted to developing P-gp inhibitors to modulate MDR. However, none of the inhibitors on the market have been successful. 1416 [1-(2,6-dimethylphenoxy)-2-(3,4-dimethoxyphenylethylamino)propane hydrochloride (phenoprolamine hydrochloride)] is a new VER (verapamil) analogue with a higher IC50 for blocking calcium channel currents than VER. In the present paper, we examined the inhibition effect of 1416 on P-gp both in vitro and in vivo. 1416 significantly enhanced cytotoxicity of VBL (vinblastine) in P-gp-overexpressed human multidrug-resistant K562/ADM (adriamycin) and KBV cells, but had no such effect on the parent K562 and KB cells. The MDR-modulating function of 1416 was further confirmed by increasing intracellular Rh123 (rhodanmine123) content in MDR cells. Human K562/ADM xenograft-nude mice model verified that 1416 potentiates the antitumour activity of VBL in vivo. RT-PCR (reverse transcriptase-PCR) and FACS analysis demonstrated that the expression of MDR1/P-gp was not affected by 1416 treatment. All these observations suggest that 1416 could be a promising agent for overcoming MDR in cancer chemotherapy.

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