Autoradiographic comparison of in vitro binding characteristics of various tritiated adenosine A2A receptor ligands in rat, mouse and pig brain and first ex vivo results

Sihver, Wiebke; Schulze, Annette; Wutz, Walter; Stüsgen, Stefan; Olsson, Ray A.; Bier, Dirk; Holschbach, M.

doi:10.1016/j.ejphar.2009.06.025

Cited by 17 publications

(20 citation statements)

References 58 publications

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“…18 F-MNI-444 distribution in the brain was consistent with known A 2A densities from autoradiography reports (26,27) and with our prior observations in the nonhuman primate brain (21). The distribution volumes estimated with the Logan graphical analysis showed a good correlation with the 1TCM and 2TCM estimates, and given the fitting issues of 1TCM in lowuptake regions and the convergence issues of 2TCM in high-uptake regions, the graphical analysis was taken as the preferred method The target-to-nontarget ratios and BP ND s measured in this study were expressively higher than those reported by other researchers using 11 C-SCH442416 and [7-methyl-11 C]-(E)-8-(3,4,5-trimethoxystyryl)-1,3,7-trimethylxanthine ( 11 C-TMSX), the other 2 PET radiotracers currently in human use.…”

Section: Discussionsupporting

confidence: 62%

“…In addition, BP ND was also estimated using the noninvasive LGA (NI-LGA) (25) with t* 5 20 min and k 2 9 5 0.15 min 21 , as well as from the SUVr (SUV ratio to the reference region) between 60 and 90 min after radiotracer injection as BP ND 5 SUVr-1. The cerebellum, shown to have low to negligible A 2A density in autoradiography experiments (26,27) and previously used in studies with A 2A radiotracers (13,14,21), was used as the reference region for data quantification. Finally, the test-retest reproducibility for V T and BP ND was estimated as ABS(test 2 retest)/AVERAGE(test 1 retest) (where ABS is absolute value).…”

Section: Brain Pet Studiesmentioning

confidence: 99%

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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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Section: Discussionsupporting

confidence: 62%

Section: Brain Pet Studiesmentioning

confidence: 99%

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

et al. 2015

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“…The determined K D values were 4.09 nM for the mA 2B AR and 0.457 nM for the rat A 2B AR. The K D value for the rA 2B AR is similar to the previously determined K D value of 0.403 nM for this radioligand for the human A 2B AR [53]. Interestingly, the K D value for the mA 2B AR was ca.…”

Section: Cloning and Expression Of Adenosine Receptorssupporting

confidence: 70%

“…The cloning of the following receptor genes was conducted: rA 1 3 H]MSX-2 determined at the mA 2A was 12.1 nM, which is in accordance with results from an autoradiography study using mouse striatum [53]. The B max value of 211 fmol/mg was not high, but similar to that determined by Klotz et al for the human A 2A AR expressed in CHO cells [49].…”

Section: Cloning and Expression Of Adenosine Receptorssupporting

confidence: 65%

Selectivity is species-dependent: Characterization of standard agonists and antagonists at human, rat, and mouse adenosine receptors

Alnouri

Jepards

Casari

et al. 2015

Purinergic Signalling

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Adenosine receptors (ARs) have emerged as new drug targets. The majority of data on affinity/potency and selectivity of AR ligands described in the literature has been obtained for the human species. However, preclinical studies are mostly performed in mouse or rat, and standard AR agonists and antagonists are frequently used for studies in rodents without knowing their selectivity in the investigated species. In the present study, we selected a set of frequently used standard AR ligands, 8 agonists and 16 antagonists, and investigated them in radioligand binding studies at all four AR subtypes, A 1 , A 2A , A 2B , and A 3 , of three species, human, rat, and mouse. Recommended, selective agonists include CCPA (for A 1 AR of rat and mouse), CGS-21680 (for A 2A AR of rat), and Cl-IB-MECA (for A 3 AR of all three species). The functionally selective partial A 2B agonist BAY60-6583 was found to additionally bind to A 1 and A 3 AR and act as an antagonist at both receptor subtypes. The antagonists PSB-36 (A 1 ), preladenant (A 2A ), and PSB-603 (A 2B ) displayed high selectivity in all three investigated species. MRS-1523 acts as a selective A 3 AR antagonist in human and rat, but is only moderately selective in mouse. The comprehensive data presented herein provide a solid basis for selecting suitable AR ligands for biological studies.

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“…The cerebellum was used as the reference region for estimation of tissue ratios and BP ND , because it had the lowest uptake and V T values of all brain regions. High-resolution autoradiography experiments have shown that the cerebellum was a region with low to negligible A 2A density in multiple species (5,24), further supporting the use of the cerebellum as a reference region. In addition, our preclinical investigations using nonhuman primates demonstrated that displacement or preblocking of 123 I-MNI-420 binding in the brain using high doses of caffeine or preladenant, respectively, did not reduce the radioactivity in the cerebellum (12), indicating that this region would be suitable as a reference region.…”

Section: Discussionmentioning

confidence: 91%

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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Autoradiographic comparison of in vitro binding characteristics of various tritiated adenosine A2A receptor ligands in rat, mouse and pig brain and first ex vivo results

Cited by 17 publications

References 58 publications

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

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

Selectivity is species-dependent: Characterization of standard agonists and antagonists at human, rat, and mouse adenosine receptors

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

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Autoradiographic comparison of in vitro binding characteristics of various tritiated adenosine A2A receptor ligands in rat, mouse and pig brain and first ex vivo results

Cited by 17 publications

References 58 publications

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

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

Selectivity is species-dependent: Characterization of standard agonists and antagonists at human, rat, and mouse adenosine receptors

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

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Product

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

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

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