(R,R)-Palonosetron Hydrochloride is the active R,R-enantiomer of Palonosetron HCl (RS25259, RS-25259 197; trade name: Aloxi and Akynzeo) which is a 5-HT3 antagonist approved in 2018 in the prevention and treatment of chemotherapy-induced nausea and vomiting. Fosnetupitant and palonosetron together have been approved by the FDA in April 2018 to prevent acute and delayed nausea and vomiting that is linked to first- and second-course highly emetogenic cancer chemotherapy. Palonosetron is a second-generation, highly selective, potent antagonist of the 5-HT3 receptor with a binding affinity for the receptor that is approximately 100 times higher than that of other antagonists of the 5-HT3 receptor (pKi 10.5 compared with 8.91 for granisetron, 8.81 for tropisetron, 8.39 for ondansetron, and 7.6 for dolasetron).

Physicochemical Properties

Molecular Formula	C19H24N2O.HCL
Molecular Weight	332.87
Exact Mass	332.17
Elemental Analysis	C, 76.99; H, 8.16; N, 9.45; O, 5.40
CAS #	135729-75-8
Related CAS #	Palonosetron hydrochloride; 135729-62-3; Palonosetron; 135729-61-2
PubChem CID	18651160
Appearance	Solid
Density	1.2±0.1 g/cm3
Boiling Point	470.4±45.0 °C at 760 mmHg
Flash Point	209.5±21.1 °C
Vapour Pressure	0.0±1.2 mmHg at 25°C
Index of Refraction	1.646
LogP	2.61
Hydrogen Bond Donor Count	1
Hydrogen Bond Acceptor Count	2
Rotatable Bond Count	1
Heavy Atom Count	23
Complexity	456
Defined Atom Stereocenter Count	2
SMILES	O=C1N(C[C@]([H])(CCC2)C3=C2C=CC=C13)[C@H]4CN5CCC4CC5.[H]Cl
InChi Key	OLDRWYVIKMSFFB-NBLXOJGSSA-N
InChi Code	InChI=1S/C19H24N2O.ClH/c22-19-16-6-2-4-14-3-1-5-15(18(14)16)11-21(19)17-12-20-9-7-13(17)8-10-20;/h2,4,6,13,15,17H,1,3,5,7-12H2;1H/t15-,17-;/m0./s1
Chemical Name	(3aR)-2-[(3R)-1-azabicyclo[2.2.2]octan-3-yl]-3a,4,5,6-tetrahydro-3H-benzo[de]isoquinolin-1-one;hydrochloride
Synonyms	(R,R)-RS 25259, RS-25233-197; RS25233-198; RS 25259 197; RS 25233-197; (R,R)-RS25233-197; RS-25233-198; RS 25233-198; RS-25259-197; (R,R)-Palonosetron hydrochloride; US brand name: Aloxi and Akynzeo
HS Tariff Code	2934.99.9001
Storage	Powder-20°C 3 years 4°C 2 years In solvent -80°C 6 months -20°C 1 month Note: Please store this product in a sealed and protected environment (e.g. under nitrogen), avoid exposure to moisture and light.
Shipping Condition	Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)

Biological Activity

Targets	5-HT3 Receptor
ln Vitro	In vitro activity: Palonosetron is a second-generation, highly selective, potent antagonist of the 5-HT3 receptor with a binding affinity for the receptor that is approximately 100 times higher than that of other antagonists of the 5-HT3 receptor (pKi 10.5 compared with 8.91 for granisetron, 8.81 for tropisetron, 8.39 for ondansetron, and 7.6 for dolasetron). Additionally, palonosetron has an extended plasma elimination half-life of about 40 hours, which is substantially longer than that of other drugs in its class (ranisetron, 8.9 hours; tropisetron, 7.3 hours; dolasetron, 7.5 hours).
ln Vivo	Quantitative autoradiographic studies in rat brain indicated a differential distribution of 5-HT3receptor sites by [3H]-RS 25259-197. High densities of sites were seen in nuclear tractus solitaris and area postrema, a medium density in spinal trigeminal tract, ventral dentate gyrus and basal medial amygdala,and a low density of sites in hippocampal CAl, parietal cortex, medium raphe and cerebellum.7 In conclusion, the functional, binding and distribution studies undertaken with the radiolabelled and non-radiolabelled RS 25259-197 (S,S enantiomer) established the profile of a highly potent and selective5-HT3 receptor antagonist[2].
Enzyme Assay	Palonosetron is a second-generation, highly selective, potent antagonist of the 5-HT3 receptor with a binding affinity for the receptor that is approximately 100 times higher than that of other antagonists of the 5-HT3 receptor (pKi 10.5 compared with 8.91 for granisetron, 8.81 for tropisetron, 8.39 for ondansetron, and 7.6 for dolasetron).
Cell Assay	Palonosetron is a 5-HT3 antagonist used to treat and prevent nausea and vomiting brought on by chemotherapy (CINV). IC50 Value: Among the 5-HT3 antagonists, 5-HT3 Receptor Palonosetron is the most successful in managing delayed CINV nausea and vomiting that manifests over a 24-hour period following the initial dosage of a chemotherapy regimen.
Animal Protocol	Autoradiographical studies[2] Coronal sections of rat and mouse brains were cut at 20 ,um thickness. Sections were dried and pre-incubated in Tris-HCl buffer (50 mM Tris, 120 mM NaCl, pH 7.4, 22°C) for 30 min. The sections were then covered with the same buffer contain- -4 ing 1.0 nM [3H]-RS 42358-197 or [3H]-RS 25259-197 for 60 min at 22°C. Non-specific binding was defined in the presence of 1.0 tLM (S)-zacopride. The incubations were ter- -n minated by rinsing the slides for two washes of 5 min in ice cold buffer. The sections were dried and apposed, together with 3H polymer standards (Amersham, Inc.) to tritiumsensitive X-ray film for 24 weeks. The autoradiograms were then analysed by digital image analysis with the MCID imaging system (Imaging Research, Inc.). Brain areas were verified on cresyl violet stained sections after autoradiography, using the areas described in the rat brain atlas of Paxinos & Watson (1985).
References	[1]. Ann Oncol . 2003 Oct;14(10):1570-7. [2]. Br J Pharmacol . 1995 Feb;114(4):851-9.

Solubility Data

Solubility (In Vitro)

DMSO: <1 mg/mL Water: ~67 mg/mL (~201.3 mM) Ethanol: <1 mg/mL

Solubility (In Vivo)

Note: Listed below are some common formulations that may be used to formulate products with low water solubility (e.g. < 1 mg/mL), you may test these formulations using a minute amount of products to avoid loss of samples. Injection Formulations (e.g. IP/IV/IM/SC) Injection Formulation 1: DMSO : Tween 80： Saline = 10 : 5 : 85 (i.e. 100 μL DMSO stock solution → 50 μL Tween 80 → 850 μL Saline) *Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH ₂ O to obtain a clear solution. Injection Formulation 2: DMSO : PEG300 ：Tween 80 : Saline = 10 : 40 : 5 : 45 (i.e. 100 μL DMSO → 400 μLPEG300 → 50 μL Tween 80 → 450 μL Saline) Injection Formulation 3: DMSO : Corn oil = 10 : 90 (i.e. 100 μL DMSO → 900 μL Corn oil) Example: Take the Injection Formulation 3 (DMSO : Corn oil = 10 : 90) as an example, if 1 mL of 2.5 mg/mL working solution is to be prepared, you can take 100 μL 25 mg/mL DMSO stock solution and add to 900 μL corn oil, mix well to obtain a clear or suspension solution (2.5 mg/mL, ready for use in animals). Injection Formulation 4: DMSO : 20% SBE-β-CD in saline = 10 : 90 [i.e. 100 μL DMSO → 900 μL (20% SBE-β-CD in saline)] *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. Injection Formulation 5: 2-Hydroxypropyl-β-cyclodextrin : Saline = 50 : 50 (i.e. 500 μL 2-Hydroxypropyl-β-cyclodextrin → 500 μL Saline) Injection Formulation 6: DMSO : PEG300 : castor oil : Saline = 5 : 10 : 20 : 65 (i.e. 50 μL DMSO → 100 μLPEG300 → 200 μL castor oil → 650 μL Saline) Injection Formulation 7: Ethanol : Cremophor : Saline = 10： 10 : 80 (i.e. 100 μL Ethanol → 100 μL Cremophor → 800 μL Saline) Injection Formulation 8: Dissolve in Cremophor/Ethanol (50 : 50), then diluted by Saline Injection Formulation 9: EtOH : Corn oil = 10 : 90 (i.e. 100 μL EtOH → 900 μL Corn oil) Injection Formulation 10: EtOH : PEG300：Tween 80 : Saline = 10 : 40 : 5 : 45 (i.e. 100 μL EtOH → 400 μLPEG300 → 50 μL Tween 80 → 450 μL Saline) Oral Formulations Oral Formulation 1: Suspend in 0.5% CMC Na (carboxymethylcellulose sodium) Oral Formulation 2: Suspend in 0.5% Carboxymethyl cellulose Example: Take the Oral Formulation 1 (Suspend in 0.5% CMC Na) as an example, if 100 mL of 2.5 mg/mL working solution is to be prepared, you can first prepare 0.5% CMC Na solution by measuring 0.5 g CMC Na and dissolve it in 100 mL ddH2O to obtain a clear solution; then add 250 mg of the product to 100 mL 0.5% CMC Na solution, to make the suspension solution (2.5 mg/mL, ready for use in animals). Oral Formulation 3: Dissolved in PEG400 Oral Formulation 4: Suspend in 0.2% Carboxymethyl cellulose Oral Formulation 5: Dissolve in 0.25% Tween 80 and 0.5% Carboxymethyl cellulose Oral Formulation 6: Mixing with food powders Note: Please be aware that the above formulations are for reference only. InvivoChem strongly recommends customers to read literature methods/protocols carefully before determining which formulation you should use for in vivo studies, as different compounds have different solubility properties and have to be formulated differently.  (Please use freshly prepared in vivo formulations for optimal results.)

Preparing Stock Solutions		1 mg	5 mg	10 mg
	1 mM	3.0042 mL	15.0209 mL	30.0418 mL
	5 mM	0.6008 mL	3.0042 mL	6.0084 mL
	10 mM	0.3004 mL	1.5021 mL	3.0042 mL

*Note: Please select an appropriate solvent for the preparation of stock solution based on your experiment needs. For most products, DMSO can be used for preparing stock solutions (e.g. 5 mM, 10 mM, or 20 mM concentration); some products with high aqueous solubility may be dissolved in water directly. Solubility information is available at the above Solubility Data section. Once the stock solution is prepared, aliquot it to routine usage volumes and store at -20°C or -80°C. Avoid repeated freeze and thaw cycles.