A2AR ( Ki = 290 nM )
Adenosine A_2A receptor agonist (hA_2A K_i = 290 nM)
Selectivity: >30-fold over A_2B and A₃ subtypes, 13-fold over A₁ subtype [1]

Regadenoson exhibits a comparatively low binding affinity (hA2A Ki=290 nM) for human A2A receptors, along with a selectivity that is over 30-fold greater than that of the A2B and A3AR subtypes, and 13-fold greater than that of the A1AR. While regadenoson acts as a full and strong agonist to cause coronary vasodilation, it acts as a weak partial agonist to cause cAMP accumulation in PC12 cells[1].

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Regadenoson shows relatively low binding affinity for human A_2A receptors (K_i = 290 nM) and greater than 30-fold selectivity versus A_2B and A₃ subtypes, and 13-fold over A₁ receptors. It is an adenosine derivative bearing an N-pyrazole at its 2-position, designed as a constrained mimetic of the E-hydrazone moiety in binodenoson. A large variation of hydrophilic and lipophilic substituents can be placed on the pyrazole ring while retaining activity at the A_2A receptor. [1]

Intravenous bolus injection of regadenoson results in a dose-dependent decrease in coronary vascular resistance and an increase in myocardial blood flow in a dog model. Regadenoson was demonstrated to cause a dose-dependent rise in heart rate and a drop in mean arterial pressure at higher dosages in a rat heart model. Additionally, serum norepinephrine and epinephrine increased by more than two times when regadenoson was administered. According to clinical data, regadenoson has an estimated clearance of 37.8 L/h and a volume of distribution of 11.5 L and 78.7 L (at steady-state). Its renal excretion accounts for 58% of its total elimination, and its terminal half-life ranges from 33 to 108 minutes[2].

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Regadenoson is approved by FDA in 2008 for myocardial perfusion imaging (MPI). It can produce a response of equivalent magnitude and a more rapid termination of action than other higher affinity agonists (e.g., CGS21680). This drug is administered as an intravenous bolus 30 seconds before the radionuclide in cardiac stress tests. [1]

Mongrel dogs (23-27 kg)
0.1, 0.175, 0.25, 0.5, 1.0, 2.5, 5 µg/kg
Peripheral intravenous injection; single

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In a dog model, the effect of caffeine on regadenoson-induced hyperemia was studied. Caffeine administration attenuated the duration of coronary vasodilation and hemodynamic changes induced by regadenoson. The specific dosing regimen of caffeine is not detailed. [2]
In a rat heart model, the mechanism of regadenoson-mediated tachycardia was investigated. Regadenoson was administered, and its effects on heart rate and blood pressure were measured. The study involved pre-treatment with pharmacological blockers (selective A_2A antagonist, beta-blocker, ganglion blocker) to dissect the mechanism. Serum catecholamine levels were also measured. Specific doses of regadenoson and the blockers are not provided in the review. [2]

Absorption, Distribution and Excretion
The pharmacokinetic characteristics of Regadenoson best conform to a three-compartment model. The time to peak concentration (Tmax) after injection is 1 to 3 minutes; the onset of pharmacodynamic response is 1 to 3 minutes; and the Emax is 12.3 ng/mL. 58% of Regadenoson is excreted via the kidneys. Central compartment: 11.5 L; steady state: 78.7 L. The mean plasma renal clearance is 450 mL/min. This value is greater than the glomerular filtration rate, suggesting tubular secretion. Metabolism/Metabolites The metabolism of Regadenoson in humans is unclear. The cytochrome P450 enzyme system is unlikely to be involved in the metabolism of Regadenoson.

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Biological half-life
Initial phase: 2–4 minutes; intermediate phase: 30 minutes (this phase is consistent with the loss of pharmacodynamic effect); terminal phase: 2 hoursThe volume of distribution of Regadenoson is 11.5 liters, 78.7 liters at steady state, and the estimated clearance is 37.8 liters/hour. It is mainly excreted by the kidneys (accounting for 58% of total clearance), with a terminal half-life of 33 to 108 minutes. Population pharmacokinetic analysis showed no correlation between model estimates and various baseline patient demographic characteristics, supporting a fixed-dose dosing regimen. No dose adjustment is required for patients with renal failure, as no adverse reactions were observed after an intravenous bolus of 400 μg in patients with serum creatinine clearance <30 ml/min. [2]
In human volunteers, the mean time to peak effect of Regadenoson (measured by intracoronary Doppler flow velocity) was 33 seconds (range 20–40 seconds). The duration of increased blood flow velocity (>2.5 times baseline) in the 400 μg and 500 μg dose groups was 2.3 min and 2.4 min, respectively. Aminophylline reversed the effects of regadenosone and reduced the duration of coronary congestion (>2-fold increase in MBF) from 6.9 min to 0.6 min. [2]

Effects During Pregnancy and Lactation
◉ Overview of Use During Lactation
There is currently no information regarding the use of legardnoxone during lactation. To avoid infant exposure to legardnoxone, breastfeeding women should avoid breastfeeding for 10 hours after administration.
◉ Effects on Breastfed Infants
No published information was found as of the revision date.
◉ Effects on Lactation and Breast Milk
No published information was found as of the revision date.

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In Phase 3 clinical trials, side effects of legardnoxone were generally mild and transient. Common adverse events included chest pain (29%), dyspnea (28%), flushing (22%), headache (23%), gastrointestinal upset (23%), dizziness (8%), and neck/jaw pain (7%). No life-threatening or serious adverse events, high-degree atrioventricular block, death, or life-threatening arrhythmias were reported. No QT interval prolongation was observed. Compared with adenosine, ligardnosone resulted in lower total symptom scores (flushing, chest pain, dyspnea). [2] In patients with mild or moderate asthma, a dose of 400 μg of ligardnosone did not result in a statistically significant change in mean FEV1 compared with placebo. The incidence of bronchospasm was 4% in both groups. No patients experienced a decrease in oxygen saturation (<92%). Dyspnea was more common in the ligardnosone group, but it was not associated with a decrease in FEV1. [2] In patients with moderate to severe chronic obstructive pulmonary disease (COPD), a dose of 400 μg of ligardnosone did not result in a statistically significant difference in mean FEV1, forced vital capacity, oxygen saturation, bronchoconstriction, or new-onset wheezing compared with placebo. Dyspnea was more common, but it was not associated with an objective decrease in lung function. [2]

[1]. J Med Chem . 2014 May 8;57(9):3623-50.

[2]. J Am Coll Cardiol . 2009 Sep 22;54(13):1123-30.

Regadenoson is a purine nucleoside. Regadenoson is an A2A adenosine receptor agonist that induces coronary artery dilation and is used for myocardial perfusion imaging. It is manufactured by Astellas Pharma and was approved by the U.S. Food and Drug Administration (FDA) on April 10, 2008. Anhydrous Regadenoson is a cardiac stress test drug. The mechanism of action of anhydrous Regadenoson is as an adenosine receptor agonist. Regadenoson is an adenosine derivative and a selective A2A adenosine receptor agonist with coronary artery dilation activity. After administration, Regadenoson selectively binds to and activates A2A adenosine receptors, thereby inducing coronary artery dilation. This leads to increased coronary blood flow and enhanced myocardial perfusion. Compared to adenosine, Regadenoson has a longer half-life and higher selectivity for A2A adenosine receptors. The drug has very weak agonistic activity against A1 adenosine receptors and negligible affinity for A2B and A3 adenosine receptors.

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Drug Indications
Diagnostic reagent for radionuclide myocardial perfusion imaging (MPI)
FDA Label
This drug is for diagnostic use only. Rapiscan is a selective coronary vasodilator intended for use in adult patients who are unable to undergo adequate exercise stress testing for radionuclide myocardial perfusion imaging (MPI).
Diagnosis of myocardial perfusion disorders

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Mechanism of Action
Ragadenosine is a selective, low-affinity (Ki = 1.3 µM) A2A receptor agonist that mimics the action of adenosine, causing coronary vasodilation and increasing myocardial blood flow. It is a very weak agonist of the A1 adenosine receptor (Ki > 16.5 µM). Furthermore, its affinity for A2B and A3 adenosine receptors is negligible. Ragadenosine is currently undergoing clinical trials for use in drug stress testing. Adenosine can slow atrioventricular nodal conduction time, block the atrioventricular nodal reentry pathway, and restore normal sinus rhythm in patients with paroxysmal supraventricular tachycardia (PSVT), including PSVT associated with Wolff-Parkinson-White syndrome.

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Pharmacodynamics
Regardnox can rapidly increase coronary blood flow (CBF), but the duration of action is short. The average peak velocity increases to more than twice the baseline level within 30 seconds and decreases to less than twice the baseline level within 10 minutes. Myocardial uptake of the radiopharmaceutical is proportional to coronary blood flow. Regardnox increases blood flow in normal coronary arteries but has no effect on narrowed (occluded) coronary arteries. The significance of this finding is that narrowed arteries absorb less radiopharmaceutical than normal coronary arteries, resulting in lower signal intensity in these areas.

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Regadenoson (also known as CVT3146) is an adenosine derivative with an N-pyrazole group attached to the 2-position, designed as a restricted mimic of the E-hydrazone moiety in Regadenoson. It was approved by the FDA in 2008 for myocardial perfusion imaging and is marketed by Astellas Pharma under the brand name Lexiscan™. It has a relatively low affinity for human A2A receptors but good pharmacokinetic properties, rapid onset of action and short duration of action, making it suitable for cardiac stress testing. [1]

C15H18N8O5

390.35402

390.14

C, 46.15; H, 4.65; N, 28.71; O, 20.49

313348-27-5

Regadenoson-d3; 313348-27-5 (free); 875148-45-1 (hydrate)

219024

Solid powder

2.0±0.1 g/cm3

158-160ºC

1.896

-3.09

5

10

4

28

587

4

OC[C@@H]1[C@H]([C@H]([C@H](N2C=NC3=C2N=C(N4N=CC(C(NC)=O)=C4)N=C3N)O1)O)O

LZPZPHGJDAGEJZ-AKAIJSEGSA-N

InChI=1S/C15H18N8O5/c1-17-13(27)6-2-19-23(3-6)15-20-11(16)8-12(21-15)22(5-18-8)14-10(26)9(25)7(4-24)28-14/h2-3,5,7,9-10,14,24-26H,4H2,1H3,(H,17,27)(H2,16,20,21)/t7-,9-,10-,14-/m1/s1

1-[6-amino-9-[(2R,3R,4S,5R)-3,4-dihydroxy-5-(hydroxymethyl)oxolan-2-yl]purin-2-yl]-N-methylpyrazole-4-carboxamide

CVT-3146; CVT 3146; CVT3146; Lexiscan

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)

DMSO: 50~78 mg/mL (128.1~199.8 mM)
Ethanol: ~2 mg/mL

Solubility in Formulation 1: ≥ 2.5 mg/mL (6.40 mM) (saturation unknown) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 400 μL PEG300 and mix evenly; then add 50 μL Tween-80 to the above solution and mix evenly; then add 450 μL normal saline to adjust the volume to 1 mL.
Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution.

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Solubility in Formulation 2: ≥ 2.5 mg/mL (6.40 mM) (saturation unknown) in 10% DMSO + 90% (20% SBE-β-CD in Saline) (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 900 μL of 20% SBE-β-CD physiological saline solution and mix evenly.
Preparation of 20% SBE-β-CD in Saline (4°C，1 week): Dissolve 2 g SBE-β-CD in 10 mL saline to obtain a clear solution.

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Solubility in Formulation 3: ≥ 2.5 mg/mL (6.40 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 900 μL of corn oil and mix evenly.

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 (Please use freshly prepared in vivo formulations for optimal results.)