Synthesis and Evaluation of No-Carrier-Added 8-Cyclopentyl-3-(3-[18F]fluoropropyl)-1-propylxanthine ([18F]CPFPX):  A Potent and Selective A1-Adenosine Receptor Antagonist for in Vivo Imaging

Holschbach, M.; Olsson, Ray A.; Bier, Dirk; Wutz, Walter; Sihver, Wiebke; Schüller, Manfred; Palm, Bettina; Coenen, Heinz H.

doi:10.1021/jm020905i

Cited by 76 publications

(50 citation statements)

References 22 publications

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“…Radiosynthesis and formulation of 18 F-CPFPX were performed as previously described (16). The mean specific radioactivity was 75.6 6 70 GBq/mmol at the start times of the scans.…”

Section: Pet Acquisitionmentioning

confidence: 99%

“…The compound 8-cyclopentyl-3-(3-fluoropropyl)-1-propylxanthine (CPFPX) (14,16) shows a high affinity for the A 1 AR (dissociation constant, 1.26 nM in cloned human receptors) and a high selectivity (A 2A adenosine receptor affinity, 940 nM). It has been applied in autoradiographic in vitro binding experiments in its tritiated form ( 3 H-CPFPX) and in PET experiments as a radiofluorinated compound ( 18 F-CPFPX) to determine A 1 AR densities in human, nonhuman primate, and rodent brain tissue.…”

mentioning

confidence: 99%

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Caffeine Occupancy of Human Cerebral A₁ Adenosine Receptors: In Vivo Quantification with ¹⁸F-CPFPX and PET

et al. 2012

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Caffeine is the neuroactive agent in coffee and tea and is a broadly consumed stimulant. It is a nonselective antagonist of the neuromodulator adenosine and, if applied in commonly consumed doses, evokes its stimulating effects through the blockade of adenosine receptors. 18 F-8-cyclopentyl-3-(3-fluoropropyl)-1-propylxanthine ( 18 F-CPFPX) has been established as a highly selective and affine PET ligand for the A 1 adenosine receptor (A 1 AR). The objective of the present study was to visualize and quantify the in vivo occupancy of the human cerebral A 1 AR by caffeine using 18 F-CPFPX and PET. Methods: Fifteen subjects (age range, 24-68 y) underwent a 140-min bolus-plus-constant-infusion PET experiment after at least 36 h of caffeine abstinence. Metabolite-corrected blood data were used to calculate steady-state distribution volumes (V T ) during the baseline condition of the scan between 70 and 90 min. Subsequently, subjects received a 10-min infusion of varying concentrations (0.5-4.3 mg/kg of body weight) of caffeine at 90 min. Occupancy V T of the A 1 AR was thereafter estimated using data acquired between 120 and 140 min. Occupancy levels were calculated using the Lassen plot, from which the inhibitory concentrations of 50% were derived. Plasma levels of caffeine were determined at regular intervals. One subject received an intravenous vehicle as a placebo. Results: Caffeine displaced 5%-44% of 18 F-CPFPX binding in a concentration-dependent manner. There was no change of radioligand binding after the administration of placebo. Halfmaximal displacement was achieved at a plasma caffeine concentration of 67 mM, which corresponds to 450 mg in a 70-kg subject or approximately 4.5 cups of coffee. Conclusion: Given a biologic half-life of about 5 h, caffeine might therefore occupy up to 50% of the cerebral A 1 AR when caffeinated beverages are repeatedly consumed during a day. Furthermore, the present study provides evidence that 18 F-CPFPX PET is suitable for studying the cerebral actions of caffeine, the most popular neurostimulant worldwide.

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“…Radiosynthesis and formulation of 18 F-CPFPX were performed as previously described (16). The mean specific radioactivity was 75.6 6 70 GBq/mmol at the start times of the scans.…”

Section: Pet Acquisitionmentioning

confidence: 99%

mentioning

confidence: 99%

Caffeine Occupancy of Human Cerebral A₁ Adenosine Receptors: In Vivo Quantification with ¹⁸F-CPFPX and PET

et al. 2012

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“…18 F]8-cyclopentyl-3-(3- (Holschbach et al, 2002;Bauer et al, 2003;Meyer et al, 2004Meyer et al, , 2005, which now allows to assess changes of A 1 ARs in vivo. [ 18 F]CPFPX is a highly affine (dissociation constant, K D ϭ 1.26 nmol/L to cloned human A 1 AR) and selective (K D ϭ 940 nmol/L for A 2A AR) compound, which shows a rapid brain uptake (time to peak within 5 min).…”

Section: Introductionmentioning

confidence: 99%

Sleep Deprivation Increases A₁Adenosine Receptor Binding in the Human Brain: A Positron Emission Tomography Study

Elmenhorst¹,

Meyer²,

Winz³

et al. 2007

J. Neurosci.

169

112

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It is currently hypothesized that adenosine is involved in the induction of sleep after prolonged wakefulness. This effect is partially reversed by the application of caffeine, which is a nonselective blocker of adenosine receptors. Here, we report that the most abundant and highly concentrated A 1 subtype of cerebral adenosine receptors is upregulated after 24 h of sleep deprivation. We used the highly selective A 1 adenosine receptor (A 1 AR) radioligand [ In sleep deprived subjects, we found an increase of the apparent equilibrium total distribution volume in a region-specific pattern in all examined brain regions with a maximum increase in the orbitofrontal cortex (15.3%; p ϭ 0.014). There were no changes in the control group with regular sleep. This is the first molecular imaging study that provides in vivo evidence for an A 1 AR upregulation in cortical and subcortical brain regions after prolonged wakefulness, indicating that A 1 AR expression is contributing to the homeostatic sleep regulation.

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“…Cerebral A 1 Rs can be visualized with PET and radiolabeled xanthine antagonists, such as 8-dicyclopropylmethyl-1-11 C-methyl-3-propylxanthine ( 11 C-MPDX) (3,4) and 8-cyclopentyl-3-[3-18 Ffluoropropyl]-1-propylxanthine ( 18 F-CPFPX) (5,6). In a previous study, we reported that 11 C-MPDX and small-animal PET can be used to quantify regional A 1 R densities in the rodent brain (7).…”

mentioning

confidence: 99%

Use of ¹¹C-MPDX and PET to Study Adenosine A₁ Receptor Occupancy by Nonradioactive Agonists and Antagonists

et al. 2014

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Adenosine A 1 receptors (A 1 Rs) in human and rodent brains can be visualized with the radioligand 8-dicyclopropylmethyl-1-11 C-methyl-3-propylxanthine ( 11 C-MPDX) and PET. Here we investigated whether A 1 R occupancy by nonradioactive agonists and antagonists can be assessed with this technique. Methods: Small-animal PET scans with arterial blood sampling were obtained for 4 groups of isoflurane-anesthetized Wistar rats: controls (n 5 7); pretreated with a centrally active A 1 R agonist, N 6 -cyclopentyladenosine (CPA; 0.25 mg/kg intraperitoneally; dissociation constant, 0.48 nM; n 5 7); pretreated with a moderate dose of caffeine (antagonist for A 1 Rs and adenosine A 2A receptors; 4 mg/kg intraperitoneally; dissociation constant, 11 mM; n 5 6); and pretreated with a high dose of caffeine (40 mg/kg intraperitoneally; n 5 6). Results: The administration of CPA resulted in a strong reduction (.50%) in the heart rate, and caffeine administration resulted in a small increase (10%-15%). A caffeine dose of 4 mg/kg (n 5 6) resulted in 65.9% A 1 R occupancy, and a dose of 40 mg/kg (n 5 6) resulted in 98.5% occupancy (calculated from a modified Lassen plot). However, the administration of CPA resulted in an increase in 11 C-MPDX binding in the brain. Conclusion: Small-animal PET with 11 C-MPDX can be used to assess antagonist but not agonist binding at A 1 Rs. Changes in tracer uptake after the administration of CPA resembled previously reported changes induced by treatment of rats with ethanol and an adenosine kinase inhibitor (ABT702). Thus, the administration of an exogenous agonist or increasing the level of an endogenous agonist have similar effects. Agonists and antagonists may bind to different sites on the A 1 R protein having allosteric interactions.

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Synthesis and Evaluation of No-Carrier-Added 8-Cyclopentyl-3-(3-[¹⁸F]fluoropropyl)-1-propylxanthine ([¹⁸F]CPFPX): A Potent and Selective A₁-Adenosine Receptor Antagonist for in Vivo Imaging

Cited by 76 publications

References 22 publications

Caffeine Occupancy of Human Cerebral A₁ Adenosine Receptors: In Vivo Quantification with ¹⁸F-CPFPX and PET

Caffeine Occupancy of Human Cerebral A₁ Adenosine Receptors: In Vivo Quantification with ¹⁸F-CPFPX and PET

Sleep Deprivation Increases A₁Adenosine Receptor Binding in the Human Brain: A Positron Emission Tomography Study

Use of ¹¹C-MPDX and PET to Study Adenosine A₁ Receptor Occupancy by Nonradioactive Agonists and Antagonists

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Synthesis and Evaluation of No-Carrier-Added 8-Cyclopentyl-3-(3-[18F]fluoropropyl)-1-propylxanthine ([18F]CPFPX): A Potent and Selective A1-Adenosine Receptor Antagonist for in Vivo Imaging

Cited by 76 publications

References 22 publications

Caffeine Occupancy of Human Cerebral A1 Adenosine Receptors: In Vivo Quantification with 18F-CPFPX and PET

Caffeine Occupancy of Human Cerebral A1 Adenosine Receptors: In Vivo Quantification with 18F-CPFPX and PET

Sleep Deprivation Increases A1Adenosine Receptor Binding in the Human Brain: A Positron Emission Tomography Study

Use of 11C-MPDX and PET to Study Adenosine A1 Receptor Occupancy by Nonradioactive Agonists and Antagonists

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Synthesis and Evaluation of No-Carrier-Added 8-Cyclopentyl-3-(3-[¹⁸F]fluoropropyl)-1-propylxanthine ([¹⁸F]CPFPX): A Potent and Selective A₁-Adenosine Receptor Antagonist for in Vivo Imaging

Caffeine Occupancy of Human Cerebral A₁ Adenosine Receptors: In Vivo Quantification with ¹⁸F-CPFPX and PET

Caffeine Occupancy of Human Cerebral A₁ Adenosine Receptors: In Vivo Quantification with ¹⁸F-CPFPX and PET

Sleep Deprivation Increases A₁Adenosine Receptor Binding in the Human Brain: A Positron Emission Tomography Study

Use of ¹¹C-MPDX and PET to Study Adenosine A₁ Receptor Occupancy by Nonradioactive Agonists and Antagonists