Synthesis and evaluation of 7-amino-2-(2(3)-furyl)-5-phenylethylamino-oxazolo[5,4-d]pyrimidines as potential A2A adenosine receptor antagonists for positron emission tomography (PET)

Holschbach, M.; Bier, Dirk; Stüsgen, Stefan; Wutz, Walter; Sihver, Wiebke; Coenen, Heinz H.; Olsson, Ray A.

doi:10.1016/j.ejmech.2005.07.018

Cited by 32 publications

(21 citation statements)

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“…Arterial blood samples (1 mL) were obtained from the ulnar or radial arteries at selected time points after radiotracer injection ( 3,6,10,30,80,120,150, and 200 min after injection were also collected for metabolite analysis. All samples were collected into ethylenediaminetetraacetic acid-coated tubes and radioactivity in whole blood and plasma assessed using a well-type g-counter with a 22-to 190-keV window (2480; Perkin Elmer Wallac).…”

Section: Brain Studiesmentioning

confidence: 99%

“…Multiple studies have demonstrated the coexpression of A 2A and D 2 dopaminergic receptors in basal ganglia neurons that are important in movement control (1,6). Furthermore, adenosine has also been implicated in neurodegeneration, and A 2A antagonists have been shown to be neuroprotective agents in experimental models of Parkinson disease (7).…”

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confidence: 99%

“…Furthermore, adenosine has also been implicated in neurodegeneration, and A 2A antagonists have been shown to be neuroprotective agents in experimental models of Parkinson disease (7). Dysregulation of A 2A function is also associated with psychiatric diseases, including mood disorders, panic disorders, schizophrenia, attention deficit hyperactivity disorder, depression, and addiction (4,6,(8)(9). Thus, in vivo imaging of A 2A using SPECT or PET would enable studies investigating disease progression and treatment response in different psychiatric and neurodegenerative disorders.…”

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confidence: 99%

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Kinetic Modeling, Test–Retest, and Dosimetry of ¹²³I-MNI-420 in Humans

et al. 2013

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In vivo imaging of adenosine 2A receptors (A 2A ) in the brain has attracted significant interest from the scientific community, because studies have shown that dysregulation of these receptors is implicated in a variety of neurodegenerative and psychiatric disorders, including Parkinson and Huntington diseases. This work aimed to describe the kinetic properties, test-retest results, and dosimetry estimates of 123 I-MNI-420, a SPECT radiotracer for the in vivo imaging of A 2A in the brain. Methods: Nine healthy human subjects were enrolled in this study; 7 completed 123 I-MNI-420 brain SPECT studies, and 2 participated in whole-body planar imaging evaluating 123 I-MNI-420 biodistribution and dosimetry. For 3 of the brain SPECT studies, arterial blood was collected for invasive modeling. Noninvasive models were also explored, including Logan graphical analysis and simplified reference tissue models. Test-retest reliability was assessed in 4 subjects. To evaluate radiotracer biodistribution and dosimetry, serial whole-body images were acquired immediately after injection and at selected time points after injection. Urine samples were collected over a period of 21 h to calculate urinary excretion. Results: 123 I-MNI-420 rapidly entered the human brain and displayed uptake consistent with known A 2A densities. At pseudoequilibrium (reached at 90 min after radiotracer injection), stable target-to-cerebellum ratios of around 1.4-2.0 were determined. Binding potentials around 0.8-1.2 were estimated using different kinetic models and the cerebellum as the reference region. Average testretest variability in the striatum was 4.8%, 3.5%, and 6.5% for the simplified reference tissue model, Logan graphical analysis, and standardized uptake value ratio methods, respectively. The estimated radiation effective dose determined from whole-body studies was 0.036 mSv/MBq. Conclusion: The data indicate that 123 I-MNI-420 is a useful SPECT radiotracer for imaging A 2A in the brain and has radiation doses that would allow for multiple scans in the same research subject each year. The availability of 123 I-MNI-420 offers the possibility of investigating A 2A activity in specific conditions and evaluating drug occupancy for A 2A candidate therapeutics.

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Section: Brain Studiesmentioning

confidence: 99%

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confidence: 99%

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Kinetic Modeling, Test–Retest, and Dosimetry of ¹²³I-MNI-420 in Humans

et al. 2013

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“…A 2A has also been identified as a promising therapeutic target in Alzheimer disease, Huntington disease, mood disorders, panic disorder, schizophrenia, attention deficit hyperactivity disorder, and addiction (5)(6)(7)(8)(9).…”

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confidence: 99%

“…The development of selective A 2A radiotracers would provide the opportunity to study and understand multiple neuropsychiatric and neurodegenerative disorders and could also accelerate and aid drug-discovery programs targeting A 2A . In this context, several compounds have been proposed for in vivo imaging of A 2A in the brain (6,(10)(11)(12)(13)(14)(15)(16)(17)(18)(19)(20).…”

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confidence: 99%

Characterization in Humans of ¹⁸F-MNI-444, a PET Radiotracer for Brain Adenosine 2A Receptors

et al. 2015

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PET with selective adenosine 2A receptor (A 2A ) radiotracers can be used to study a variety of neurodegenerative and neuropsychiatric disorders in vivo and to support drug-discovery studies targeting A 2A . The aim of this study was to describe the first in vivo evaluation of 18 F-MNI-444, a novel PET radiotracer for imaging A 2A , in healthy human subjects. Methods: Ten healthy human volunteers were enrolled in this study; 6 completed the brain PET studies and 4 participated in the whole-body PET studies. Arterial blood was collected for invasive kinetic modeling of the brain PET data. Noninvasive methods of data quantification were also explored. Test-retest reproducibility was evaluated in 5 subjects. Radiotracer distribution and dosimetry was determined using serial whole-body PET images acquired over 6 h post-radiotracer injection. Urine samples were collected to calculate urinary excretion. Results: After intravenous bolus injection, 18 F-MNI-444 rapidly entered the brain and displayed a distribution consistent with known A 2A densities in the brain. Binding potentials ranging from 2.6 to 4.9 were measured in A 2A -rich regions, with an average test-retest variability of less than 10%. The estimated whole-body radiation effective dose was approximately 0.023 mSv/MBq. Conclusion: 18 F-MNI-444 is a useful PET radiotracer for imaging A 2A in the human brain. The superior in vivo brain kinetic properties of 18 F-MNI-444, compared with previously developed A 2A radiotracers, provide the opportunity to foster global use of in vivo A 2A PET imaging in neuroscience research.

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