Identification

Name
Fluciclovine (18F)
Accession Number
DB13146
Type
Small Molecule
Groups
Approved
Description

Fluciclovine is a [18F]-tagged synthetic analog of the amino acid L-leucine. It presents excellent diagnostic properties to be used in positron emission tomography (PET) imaging.[2] The structure of fluciclovine allows it to be uptaken by the tumoral cells by its amino acid transporter without incorporating in the metabolism within the body.[3] Fluciclovine was developed by Blue Earth Diagnostics, Ltd. and FDA approved in May 27, 2016.[7]

Structure
Thumb
Synonyms
  • (18F)FACBC
  • (1R,3R)-1-amino-3(18F)fluorocyclobutane-1-carboxylic acid
  • Anti-1-amino-3-(18F)fluorocyclobutane-1-carboxylic acid
  • FACBC F-18
  • Fluciclovine F 18
  • Fluciclovine F-18
External IDs
(18F)GE-148 / GE-148 (18F) / GE-148 F-18 / NMK-36 / NMK36
Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing End
AxuminInjection, solution221 mCi/1mLIntravenousBlue Earth Diagnostics2016-05-27Not applicableUs
Categories
UNII
38R1Q0L1ZE
CAS number
222727-39-1
Weight
Average: 132.125
Monoisotopic: 132.056441169
Chemical Formula
C5H8FNO2
InChI Key
NTEDWGYJNHZKQW-DGMDOPGDSA-N
InChI
InChI=1S/C5H8FNO2/c6-3-1-5(7,2-3)4(8)9/h3H,1-2,7H2,(H,8,9)/t3-,5-/i6-1
IUPAC Name
(1r,3r)-1-amino-3-(¹⁸F)fluorocyclobutane-1-carboxylic acid
SMILES
N[C@]1(C[C@H]([18F])C1)C(O)=O

Pharmacology

Indication

Fluciclovine is indicated as a detection agent for positron emission tomography (PET) in men with suspected prostate cancer recurrence based on elevated blood prostate specific antigen (PSA) levels following prior treatment.[4] The overexpression of L-type amino acid transporters such as LAT1 and LAT3 that mediate the uptake of essential amino acids has been extensively reported as a tumoral mechanism of cell growth.[5]

Associated Conditions
Pharmacodynamics

Following intravenous administration, the tumor-to-normal tissue contrast is highest between 2 and 10 minutes after injection, with a 63% reduction in mean tumor uptake at 90 minutes after injection.[6] The scanning time point should be evaluated carefully as an early scanning can present an increased blood pool and a late scanning will translate into an increased muscle uptake. These variations should always be considered in the image interpretation.[8]

Mechanism of action

Fluciclovine is transported into the prostate cancer cells via ASCT2 and LAT1 transporters. The activity of LAT1 gets increased in acidic pH, condition that is developed intra-tumorally at certain size. The uptake of fluciclovine presents an androgen-dependent dynamic in hormone sensitive cells.[9]

TargetActionsOrganism
ANeutral amino acid transporter B(0)
binder
Human
AY+L amino acid transporter 1
binder
Human
ACationic amino acid transporter 3
binder
Human
NGlutamate (NMDA) receptor
inhibitor
Human
NGlutamate receptor 1
inhibitor
Human
NGlutamate receptor 2
inhibitor
Human
NGlutamate receptor 3
inhibitor
Human
NGlutamate receptor 4
inhibitor
Human
Absorption

After intravenous administration of fluciclovine, the major distribution happens in liver (14%), red bone marrow (12%), lung (7%), myocardium (4%) and pancreas (3%). With increasing time, the dose gets distributed into skeletal muscle.[9]

Volume of distribution

The compartmental volume of distribution of fluciclovine is in prostate 0.97 L, vesicle 0.79 L, red bone marrow 0.98 L, gluteus muscle 2.13 L and obturator muscle 2.23 L.[6]

Protein binding

Pre clinical studies showed that fluciclovine does not bind to plasma proteins.[10]

Metabolism

Fluciclovine is not metabolized and it is not incorporated into newly synthesized proteins.[9]

Route of elimination

In the first four hours post-injection, 3% of administered dose is excreted in the urine which increases to 5% after 24 hours post-injection.[9]

Half life

Fluciclovine is a cyclotron produced radionuclide that decays by positron emission (ß+ decay, 96.7%) and orbital electron capture (3.3%) to stable oxygen 18 with a physical half-life of 109.7 minutes.[1]

Clearance

Fluciclovine renal clearance and excretion is minimal.[6]

Toxicity

The hasn't been long-term carcinogenity or fertility studies in animals. Even though all reports have shown no mutagenicity, fluciclovine has the potential to be mutagenic.[10]

Affected organisms
  • Humans and other mammals
Pathways
Not Available
Pharmacogenomic Effects/ADRs
Not Available

Interactions

Drug Interactions
DrugInteraction
AbemaciclibThe serum concentration of Fluciclovine (18F) can be increased when it is combined with Abemaciclib.
AcetaminophenThe serum concentration of Fluciclovine (18F) can be increased when it is combined with Acetaminophen.
AfatinibThe serum concentration of Fluciclovine (18F) can be increased when it is combined with Afatinib.
AlbendazoleThe serum concentration of Fluciclovine (18F) can be increased when it is combined with Albendazole.
AldosteroneThe serum concentration of Fluciclovine (18F) can be decreased when it is combined with Aldosterone.
AlectinibThe serum concentration of Fluciclovine (18F) can be increased when it is combined with Alectinib.
AmiodaroneThe serum concentration of Fluciclovine (18F) can be increased when it is combined with Amiodarone.
AmlodipineThe serum concentration of Fluciclovine (18F) can be increased when it is combined with Amlodipine.
AmodiaquineThe serum concentration of Fluciclovine (18F) can be increased when it is combined with Amodiaquine.
AmoxapineThe serum concentration of Fluciclovine (18F) can be increased when it is combined with Amoxapine.
Food Interactions
Not Available

References

General References
  1. Nye JA, Schuster DM, Yu W, Camp VM, Goodman MM, Votaw JR: Biodistribution and radiation dosimetry of the synthetic nonmetabolized amino acid analogue anti-18F-FACBC in humans. J Nucl Med. 2007 Jun;48(6):1017-20. doi: 10.2967/jnumed.107.040097. Epub 2007 May 15. [PubMed:17504867]
  2. Schuster DM, Votaw JR, Nieh PT, Yu W, Nye JA, Master V, Bowman FD, Issa MM, Goodman MM: Initial experience with the radiotracer anti-1-amino-3-18F-fluorocyclobutane-1-carboxylic acid with PET/CT in prostate carcinoma. J Nucl Med. 2007 Jan;48(1):56-63. [PubMed:17204699]
  3. Schiavina R, Brunocilla E, Martorana G: The new promise of FACBC position emission tomography/computed tomography in the localization of disease relapse after radical treatment for prostate cancer: are we turning to the right radiotracer? Eur Urol. 2014 Jan;65(1):255-6. doi: 10.1016/j.eururo.2013.08.053. Epub 2013 Aug 30. [PubMed:24094575]
  4. Schuster DM, Nanni C, Fanti S: PET Tracers Beyond FDG in Prostate Cancer. Semin Nucl Med. 2016 Nov;46(6):507-521. doi: 10.1053/j.semnuclmed.2016.07.005. Epub 2016 Sep 7. [PubMed:27825431]
  5. Wang Q, Bailey CG, Ng C, Tiffen J, Thoeng A, Minhas V, Lehman ML, Hendy SC, Buchanan G, Nelson CC, Rasko JE, Holst J: Androgen receptor and nutrient signaling pathways coordinate the demand for increased amino acid transport during prostate cancer progression. Cancer Res. 2011 Dec 15;71(24):7525-36. doi: 10.1158/0008-5472.CAN-11-1821. Epub 2011 Oct 17. [PubMed:22007000]
  6. Sorensen J, Owenius R, Lax M, Johansson S: Regional distribution and kinetics of [18F]fluciclovine (anti-[18F]FACBC), a tracer of amino acid transport, in subjects with primary prostate cancer. Eur J Nucl Med Mol Imaging. 2013 Feb;40(3):394-402. doi: 10.1007/s00259-012-2291-9. Epub 2012 Dec 4. [PubMed:23208700]
  7. FDA News and Events [Link]
  8. Axumin [Link]
  9. Axumin [Link]
  10. FDA Reports [Link]
External Links
PubChem Compound
450601
PubChem Substance
347829262
ChemSpider
23313216
ChEBI
134703
ChEMBL
CHEMBL254468
Wikipedia
Fluciclovine
FDA label
Download (265 KB)
MSDS
Download (116 KB)

Clinical Trials

Clinical Trials
PhaseStatusPurposeConditionsCount
0RecruitingOtherProstate Cancer1
2Active Not RecruitingDiagnosticRecurrent Prostate Carcinoma1
2CompletedDiagnosticProstate Cancer1
2RecruitingDiagnosticMalignancies1
2RecruitingDiagnosticMetastatic Hormone Refractory Prostate Cancer / Prostate Carcinoma Metastatic in the Bone / Stage IV Prostate Cancer1
2RecruitingDiagnosticProstate Cancer1
2TerminatedDiagnosticProstate Cancer1
4Not Yet RecruitingDiagnosticCervical Cancers / Endometrial Cancers / Ovarian Epithelial Cancer1

Pharmacoeconomics

Manufacturers
Not Available
Packagers
Not Available
Dosage forms
FormRouteStrength
Injection, solutionIntravenous221 mCi/1mL
Prices
Not Available
Patents
Patent NumberPediatric ExtensionApprovedExpires (estimated)
US5808146No1998-09-152017-11-09Us
US9387266No2016-07-122026-11-28Us
US10010632No2006-11-282026-11-28Us

Properties

State
Liquid
Experimental Properties
PropertyValueSource
melting point (°C)0ºCMSDS
boiling point (°C)100ºCMSDS
water solubilitySolubleMSDS
Radioactivity (mCi/mL)10FDA label
Predicted Properties
PropertyValueSource
Water Solubility173.0 mg/mLALOGPS
logP-3ALOGPS
logP-2.9ChemAxon
logS0.11ALOGPS
pKa (Strongest Acidic)2.07ChemAxon
pKa (Strongest Basic)9.42ChemAxon
Physiological Charge0ChemAxon
Hydrogen Acceptor Count3ChemAxon
Hydrogen Donor Count2ChemAxon
Polar Surface Area63.32 Å2ChemAxon
Rotatable Bond Count1ChemAxon
Refractivity27.75 m3·mol-1ChemAxon
Polarizability11.65 Å3ChemAxon
Number of Rings1ChemAxon
Bioavailability1ChemAxon
Rule of FiveYesChemAxon
Ghose FilterNoChemAxon
Veber's RuleNoChemAxon
MDDR-like RuleNoChemAxon
Predicted ADMET features
Not Available

Spectra

Mass Spec (NIST)
Not Available
Spectra
SpectrumSpectrum TypeSplash Key
Predicted GC-MS Spectrum - GC-MSPredicted GC-MSNot Available
Predicted MS/MS Spectrum - 10V, Positive (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 20V, Positive (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 40V, Positive (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 10V, Negative (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 20V, Negative (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 40V, Negative (Annotated)Predicted LC-MS/MSNot Available

Taxonomy

Description
This compound belongs to the class of organic compounds known as l-alpha-amino acids. These are alpha amino acids which have the L-configuration of the alpha-carbon atom.
Kingdom
Organic compounds
Super Class
Organic acids and derivatives
Class
Carboxylic acids and derivatives
Sub Class
Amino acids, peptides, and analogues
Direct Parent
L-alpha-amino acids
Alternative Parents
D-alpha-amino acids / Amino acids / Monocarboxylic acids and derivatives / Carboxylic acids / Organofluorides / Organic oxides / Monoalkylamines / Hydrocarbon derivatives / Carbonyl compounds / Alkyl fluorides
Substituents
D-alpha-amino acid / L-alpha-amino acid / Amino acid / Carboxylic acid / Monocarboxylic acid or derivatives / Alkyl fluoride / Hydrocarbon derivative / Organic oxide / Primary amine / Organooxygen compound
Molecular Framework
Aliphatic homomonocyclic compounds
External Descriptors
Not Available

Targets

Kind
Protein
Organism
Human
Pharmacological action
Yes
Actions
Binder
General Function
Virus receptor activity
Specific Function
Sodium-dependent amino acids transporter that has a broad substrate specificity, with a preference for zwitterionic amino acids. It accepts as substrates all neutral amino acids, including glutamin...
Gene Name
SLC1A5
Uniprot ID
Q15758
Uniprot Name
Neutral amino acid transporter B(0)
Molecular Weight
56597.64 Da
References
  1. Axumin [Link]
Kind
Protein
Organism
Human
Pharmacological action
Yes
Actions
Binder
General Function
L-amino acid transmembrane transporter activity
Specific Function
Involved in the sodium-independent uptake of dibasic amino acids and sodium-dependent uptake of some neutral amino acids. Requires coexpression with SLC3A2/4F2hc to mediate the uptake of arginine, ...
Gene Name
SLC7A7
Uniprot ID
Q9UM01
Uniprot Name
Y+L amino acid transporter 1
Molecular Weight
55990.01 Da
References
  1. Axumin [Link]
Kind
Protein
Organism
Human
Pharmacological action
Yes
Actions
Binder
General Function
L-ornithine transmembrane transporter activity
Specific Function
Mediates the uptake of the cationic amino acids arginine, lysine and ornithine in a sodium-independent manner.
Gene Name
SLC7A3
Uniprot ID
Q8WY07
Uniprot Name
Cationic amino acid transporter 3
Molecular Weight
67168.31 Da
References
  1. Axumin [Link]
Kind
Protein group
Organism
Human
Pharmacological action
No
Actions
Inhibitor
General Function
Voltage-gated cation channel activity
Specific Function
NMDA receptor subtype of glutamate-gated ion channels with high calcium permeability and voltage-dependent sensitivity to magnesium. Mediated by glycine. This protein plays a key role in synaptic p...

Components:
References
  1. FDA Reports [Link]
Kind
Protein
Organism
Human
Pharmacological action
No
Actions
Inhibitor
General Function
Pdz domain binding
Specific Function
Ionotropic glutamate receptor. L-glutamate acts as an excitatory neurotransmitter at many synapses in the central nervous system. Binding of the excitatory neurotransmitter L-glutamate induces a co...
Gene Name
GRIA1
Uniprot ID
P42261
Uniprot Name
Glutamate receptor 1
Molecular Weight
101505.245 Da
References
  1. FDA Reports [Link]
Kind
Protein
Organism
Human
Pharmacological action
No
Actions
Inhibitor
General Function
Ionotropic glutamate receptor activity
Specific Function
Receptor for glutamate that functions as ligand-gated ion channel in the central nervous system and plays an important role in excitatory synaptic transmission. L-glutamate acts as an excitatory ne...
Gene Name
GRIA2
Uniprot ID
P42262
Uniprot Name
Glutamate receptor 2
Molecular Weight
98820.32 Da
References
  1. FDA Reports [Link]
Kind
Protein
Organism
Human
Pharmacological action
No
Actions
Inhibitor
General Function
Extracellular-glutamate-gated ion channel activity
Specific Function
Receptor for glutamate that functions as ligand-gated ion channel in the central nervous system and plays an important role in excitatory synaptic transmission. L-glutamate acts as an excitatory ne...
Gene Name
GRIA3
Uniprot ID
P42263
Uniprot Name
Glutamate receptor 3
Molecular Weight
101155.975 Da
References
  1. FDA Reports [Link]
Kind
Protein
Organism
Human
Pharmacological action
No
Actions
Inhibitor
General Function
Ionotropic glutamate receptor activity
Specific Function
Receptor for glutamate that functions as ligand-gated ion channel in the central nervous system and plays an important role in excitatory synaptic transmission. L-glutamate acts as an excitatory ne...
Gene Name
GRIA4
Uniprot ID
P48058
Uniprot Name
Glutamate receptor 4
Molecular Weight
100870.085 Da
References
  1. FDA Reports [Link]

Transporters

Kind
Protein
Organism
Human
Pharmacological action
No
Actions
Substrate
General Function
Xenobiotic-transporting atpase activity
Specific Function
Energy-dependent efflux pump responsible for decreased drug accumulation in multidrug-resistant cells.
Gene Name
ABCB1
Uniprot ID
P08183
Uniprot Name
Multidrug resistance protein 1
Molecular Weight
141477.255 Da
References
  1. FDA Reports [Link]
Kind
Protein
Organism
Human
Pharmacological action
No
Actions
Substrate
General Function
Atpase activity, coupled to transmembrane movement of substances
Specific Function
May be an organic anion pump relevant to cellular detoxification.
Gene Name
ABCC4
Uniprot ID
O15439
Uniprot Name
Multidrug resistance-associated protein 4
Molecular Weight
149525.33 Da
References
  1. FDA Reports [Link]

Drug created on November 16, 2016 08:20 / Updated on November 02, 2018 07:34