scholarly journals Synthesis and In Vitro Evaluation of 8-Pyridinyl-Substituted Benzo[e]imidazo[2,1-c][1,2,4]triazines as Phosphodiesterase 2A Inhibitors

Molecules ◽  
2019 ◽  
Vol 24 (15) ◽  
pp. 2791 ◽  
Author(s):  
Ritawidya ◽  
Ludwig ◽  
Briel ◽  
Brust ◽  
Scheunemann
Keyword(s):  
Potent Inhibitor ◽  
Liver Microsomes ◽  
Emission Tomography ◽  
Inhibitory Potency ◽  
Positron Emission ◽  
Neuropsychiatric Diseases ◽  
Further Development ◽  
The Brain

Phosphodiesterase 2A (PDE2A) is highly expressed in distinct areas of the brain, which are known to be related to neuropsychiatric diseases. The development of suitable PDE2A tracers for Positron Emission Tomography (PET) would permit the in vivo imaging of the PDE2A and evaluation of disease-mediated alterations of its expression. A series of novel fluorinated PDE2A inhibitors on the basis of a Benzoimidazotriazine (BIT) scaffold was prepared leading to a prospective inhibitor for further development of a PDE2A PET imaging agent. BIT derivatives (BIT1–9) were obtained by a seven-step synthesis route, and their inhibitory potency towards PDE2A and selectivity over other PDEs were evaluated. BIT1 demonstrated much higher inhibition than other BIT derivatives (82.9% inhibition of PDE2A at 10 nM). BIT1 displayed an IC50 for PDE2A of 3.33 nM with 16-fold selectivity over PDE10A. This finding revealed that a derivative bearing both a 2-fluoro-pyridin-4-yl and 2-chloro-5-methoxy-phenyl unit at the 8- and 1-position, respectively, appeared to be the most potent inhibitor. In vitro studies of BIT1 using mouse liver microsomes (MLM) disclosed BIT1 as a suitable ligand for 18F-labeling. Nevertheless, future in vivo metabolism studies are required.

In vivo neuropharmacology of schizophrenia

1999 ◽  
Vol 174 (S38) ◽  
pp. 23-33 ◽  
Author(s):  
V. Bigliani ◽  
L. S. Pilowsky
Keyword(s):  
Single Photon ◽  
Photon Emission ◽  
Emission Tomography ◽  
Binding Assays ◽  
Single Photon Emission ◽  
Positron Emission ◽  
The Brain ◽  
Major Target

Since the introduction of chlorpromazine in the 1950s, followed by the discovery (with in vitro receptor binding assays), in the mid-1970s, that antipsychotic drugs block a subtype of dopamine receptor (D2/D2-like) (Creese et al, 1976) and that affinity for these receptors appears to correlate directly with clinical potency for antipsychotics (Peroutka & Synder, 1980), the study of neurotransmitters and receptors has been a major target of schizophrenia research (Owens, 1996). In 1983, the first visualisation, by positron emission tomography (PET), of the binding of D2 dopamine receptors in the brain of a living human subject was reported (Wagner et al, 1983). Following this, the number of research studies using PET and single photon emission tomography (SPET) has increased enormously.

scholarly journals Development of a blood sample detector for multi-tracer positron emission tomography using gamma spectroscopy

2019 ◽  
Vol 6 (1) ◽  
Author(s):  
Carlos Velasco ◽  
Adriana Mota-Cobián ◽  
Jesús Mateo ◽  
Samuel España
Keyword(s):  
Positron Emission Tomography ◽  
Blood Sample ◽  
Pet Imaging ◽  
Spectroscopic Analysis ◽  
Gamma Spectroscopy ◽  
Emission Tomography ◽  
Blood Samples ◽  
Positron Emission

Abstract Background Multi-tracer positron emission tomography (PET) imaging can be accomplished by applying multi-tracer compartment modeling. Recently, a method has been proposed in which the arterial input functions (AIFs) of the multi-tracer PET scan are explicitly derived. For that purpose, a gamma spectroscopic analysis is performed on blood samples manually withdrawn from the patient when at least one of the co-injected tracers is based on a non-pure positron emitter. Alternatively, these blood samples required for the spectroscopic analysis may be obtained and analyzed on site by an automated detection device, thus minimizing analysis time and radiation exposure of the operating personnel. In this work, a new automated blood sample detector based on silicon photomultipliers (SiPMs) for single- and multi-tracer PET imaging is presented, characterized, and tested in vitro and in vivo. Results The detector presented in this work stores and analyzes on-the-fly single and coincidence detected events. A sensitivity of 22.6 cps/(kBq/mL) and 1.7 cps/(kBq/mL) was obtained for single and coincidence events respectively. An energy resolution of 35% full-width-half-maximum (FWHM) at 511 keV and a minimum detectable activity of 0.30 ± 0.08 kBq/mL in single mode were obtained. The in vivo AIFs obtained with the detector show an excellent Pearson’s correlation (r = 0.996, p < 0.0001) with the ones obtained from well counter analysis of discrete blood samples. Moreover, in vitro experiments demonstrate the capability of the detector to apply the gamma spectroscopic analysis on a mixture of 68Ga and 18F and separate the individual signal emitted from each one. Conclusions Characterization and in vivo evaluation under realistic experimental conditions showed that the detector proposed in this work offers excellent sensibility and stability. The device also showed to successfully separate individual signals emitted from a mixture of radioisotopes. Therefore, the blood sample detector presented in this study allows fully automatic AIFs measurements during single- and multi-tracer PET studies.

scholarly journals Anatomic and Biochemical Correlates of the Dopamine Transporter Ligand 11C-PE2I in Normal and Parkinsonian Primates: Comparison with 6-[18F]Fluoro-L-Dopa

2001 ◽  
Vol 21 (7) ◽  
pp. 782-792 ◽  
Author(s):  
Thomas Poyot ◽  
Françoise Condé ◽  
Marie-Claude Grégoire ◽  
Vincent Frouin ◽  
Christine Coulon ◽  
...  
Keyword(s):  
Gold Standard ◽  
Dopaminergic Neurons ◽  
Emission Tomography ◽  
Attractive Alternative ◽  
Input Rate ◽  
Nigrostriatal Pathway ◽  
Positron Emission ◽  
Neuroprotective Strategies

Positron emission tomography (PET) coupled to 6-[18F]Fluoro-L-Dopa (18F-Dopa) remains the gold standard for assessing dysfunctionality concerning the dopaminergic nigrostriatal pathway in Parkinson's disease and related disorders. The use of ligands of the dopamine transporters (DAT) is an attractive alternative target; consequently, the current aim was to validate one of them, 11C-PE2I, using a multiinjection modeling approach allowing accurate quantitation of DAT densities in the striatum. Experiments were performed in three controls, three MPTP-treated (parkinsonian) baboons, and one reserpine-treated baboon. 11C-PE2I B′max values obtained with this approach were compared with 18F-Dopa input rate constant values (Ki), in vitro Bmax binding of 125I-PE2I, and the number of dopaminergic neurons in the substantia nigra estimated postmortem by stereology. In the caudate nucleus and putamen, control values for 11C-PE2I B'max were 673 and 658 pmol/mL, respectively, whereas it was strongly reduced in the MPTP-treated (B′max = 26 and 36 pmol/mL) and reserpine-treated animals (B′max = 338 and 483 pmol/mL). In vivo11C-PE2I B′max values correlated with 18F-Dopa Ki values and in vitro125I-PE2I Bmax values in the striatum and with the number of nigral dopaminergic neurons. Altogether, these data support the use of 11C-PE2I for monitoring striatal dopaminergic disorders and the effect of potential neuroprotective strategies.

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