Download NH3 N]ammonia

NH3
[13N]ammonia
Radiopharmaceutical Name
13
Radiopharmaceutical Image
Normal 13NH3 Stress / Rest
NH3, 13N-ammonia , [13N]NH3
Abbreviations: NH3, N-13 ammonia
Normal Biodistribution
Radiopharmaceutical Structure
The circulation mean transit time of 13N ammonia
from the circulation is 1.08 minutes, 0.064 of the
administered activity returns to the circulation as
metabolites with a half-time of approximately 2
minutes.
Approximately, 7.1% and 6.9% are taken up in
liver and brain, respectively. Approximately 6.4%
enters the urinary bladder with a half-time of 8
minutes.
(ICRP Publication 53,1994)
image courtesy of James. H Caldwell, MD University of
Washington
Radionuclide
13
N
Half-life 9.965 minutes
Emission
Emission positron: Emax 0.492 MeV
MICAD
http://www.ncbi.nlm.nih.gov/pubmed/books/NBK23075/ pdf/AmmoniaN13.pdf
Developed by the SNMMI PET Center of Excellence and the Center for Molecular Imaging Innovation & Translation
December 2012 - 1
NH3
[13N]ammonia
Molecular Formula and Weight
13
General Tracer Class
Clinical Diagnostic PET Radiopharmaceutical
Target
In vivo, 13NH3 is in the form of ammonium ion. After IV injection it is extracted from the capillaries through the
ammonia transporter. Once in cells, it is converted to glutamine and can diffuse out of the cell or be metabolized
to glutamate and retained within the cell. Targets all viable tissue that has blood flow but the clinical target is
myocardial perfusion. (References: Khademi et al. 2004, Adeva et al. 2012, Feinstein Institute for Medical
Research, Highlights of Prescribing Information for Ammonia 13N Injection for intravenous use 2011)
Molecular Process Imaged
Blood vessel perfusion of tissues in general proportional to blood flow.
Mechanism for in vivo retention
Enters cell via the ammonium transporter with accumulation in tissue in proportion to blood perfusion of the
tissue. Retention is due to the ammonium conversion to glutamate or other metabolites (References: Khademi et
al. 2004, Adeva et al. 2012, Feinstein Institute for Medical Research, Highlights of Prescribing Information for
Ammonia 13N Injection for intravenous use 2011)
Metabolism
13
N-ammonia undergoes a five-enzyme step metabolism in the liver to yield 13N-urea, the main circulating
metabolite. It is also metabolized to 13N-glutamine, the main metabolite in tissues, by glutamine synthase in the
skeletal muscles, liver, brain, myocardium, and other organs. Other metabolites of 13N-ammonia include small
amounts of 13N-amino acid anions (acidic amino acids) in the forms of 13N-glutamate or 13N-aspartate. 13Nammonia is eliminated from the body by urinary excretion mainly as 13N-urea. (Feinstein Institute for Medical
Research, Highlights of Prescribing Information for 13N-ammonia Injection for intravenous use 2011). With
exercise, some ammonia may be released from skeletal muscle to the vessels (Adeva 2012)
Radiosynthesis
Most sites use a synthesis method reported by Berridge (1993) in which water containing a small amount of
ethanol is irradiated with protons in a nuclear reaction followed by a radiation chemistry process to form the
13
NH4+ (ammonium ion) in the target.
Additional information available at Molecular Imaging and Contrast Agent Database (MICAD), Bethesda (MD):
National Center for Biotechnology Information http://www.ncbi.nlm.nih.gov/pubmed/books/NBK23075/
pdf/AmmoniaN13.pdf for [13N]ammonia, author Cheng.
Availability
The short half-life of 13N requires a nearby cyclotron. As for any PET radiopharmaceutical, an IND, NDA or
NH3
16.02 g atom mole-1
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December 2012 - 2
NH3
[13N]ammonia
ANDA filed with the Food and Drug Administration (FDA) is required for human use.*
Status with USP / EuPh
The radiopharmaceutical is approved by the FDA, and is listed in USP and EuPh.
Recommended Activity and Allowable mass
DOSAGE AND ADMINISTRATION (taken from Prescribing Information)
IV administration, typically 10-20 mCi (370 – 740 MBq) as a bolus (Feinstein Institute for Medical Research,
Highlights of Prescribing Information for Ammonia 13N Injection for intravenous use 2011)
Dosimetry
The effective dose equivalent (whole body) is estimated to be 0.0027 mSv/MBq (10 mrem/mCi) for adults.
The critical organs are the kidneys, which receive 0.0046 mGy/MBq (17 mrad/mCi) for adults (ICRP Publication
No. 53 1994). Additional radiation absorbed dose information is provided in the ICRP publication and in the
Feinstein Institute for Medical Research, Highlights of Prescribing Information for Ammonia 13N Injection for
intravenous use.).
Pharmacology and Toxicology
Following intravenous injection, 13N-ammonia is cleared rapidly from the
blood with a biologic half-life of about 2.84 minutes (effective half-life of about 2.2
minutes). In the myocardium, its biologic half-life has been estimated to be less than 2 minutes (effective half-life
less than 1.67 minutes). In the brain its biologic half-life is less than 3 seconds.
The mass of 13N-ammonia injected for imaging is very small compared to the normal range of ammonia in the
blood (0.72 – 3.30 mg) in a 70 kg healthy adult man.
Current Clinical Trials
Reference Site / Person
Imaging Protocol
Reference: Feinstein Institute for Medical Research, Highlights of Prescribing Information for Ammonia 13N
Injection for intravenous use.
The NIH clinical trials registry (www.clinicaltrials.gov) should be consulted for a list of current trials using 13Nammonia. As of December 2012, three clinical trials were listed for the United States, only one that was still
accruing patients.
The best reference at this time for the state of 13NH3 trials is clinical trials.gov
The imaging protocol for 13N-ammonia can vary. A typical example is:
Rest Imaging Study :
• Administer 10-20 mCi (370 – 740 MBq) as a bolus through a catheter inserted into a large peripheral vein.
• Start imaging 3 minutes after the injection and acquire images for a total of 10-20 minutes.
Stress Imaging Study:
• If a rest imaging study is performed, begin the stress imaging study 40 minutes or more after the first 13Nammonia injection to allow sufficient isotope decay.
• Administer a pharmacologic stress-inducing drug in accordance with its labeling.
• Administer 10-20 mCi (370 – 740 MBq) of 13N-ammonia as a bolus at peak stress (exact time point may vary
depending on stress agent, for instance at 7 min when dipyridamole as stress agent is given over 4 min IV, i.e. 3
Developed by the SNMMI PET Center of Excellence and the Center for Molecular Imaging Innovation & Translation
December 2012 - 3
NH3
[13N]ammonia
min after the completion of dipyridamole).
• Start imaging 3 minutes after the injection of 13N-ammonia and acquire images for a total of 10-20 minutes.
Reference: Feinstein Institute for Medical Research, Highlights of Prescribing Information for Ammonia 13N
Injection for intravenous use.
Recent work indicates that dynamic imaging provides added useful clinical data because the time activity curves
can be analyzed to quantify myocardial blood flow, and provide information on myocardial flow reserve in
addition to the semi-quantitative results of static perfusion image analysis. (Alesssio 2012, Beller 2012, Fiechter
2012, Herzog 2009, Murthy 2012a /b, Saraste 2012).
Human Imaging Experience
•
IND is an investigational new drug application, NDA is new drug application, ANDA is an amended new
drug application.
Listed below are selected references for 13N-ammonia injection. Because this is a drug that is administered
primarily as a clinical drug under NDA with the FDA, the principle reference that is provided is the prescribing
information available on the FDA website.
Adeva MM et al. Ammonium Metabolism in Humans. Metabolism 2012; 61:1495-1511.
Alessio AM et al. Validation of an axially distributed model for quantification of myocardial blood flow
using 13N-ammonia PET. J Nucl Cardiol 2013; 20:64-75.
Beller G. Quantification of myocardial blood flow with PET: Ready for clinical application. Editorial. J
Nucl Cardiol 2012; 19:877-878.
Berridge MS et al. In-target Production of [13N]Ammonia: Target Design, Products and Operating
Parameters. Appl Radiat Isot 1993; 44 (12) 1433-1441.
Cheng, KT. [13N]Ammonia. Molecular Imaging and Contrast Agent Database (MICAD), Bethesda (MD):
National Center for Biotechnology Information http://www.ncbi.nlm.nih.gov/pubmed/books/NBK23075/
pdf/AmmoniaN13.pdf
Feinstein Institute for Medical Research (Chaly T). Highlights of Prescribing Information for Ammonia N
13 Injection for intravenous Use. 2011, Initial approval 2007
http://www.accessdata.fda.gov/drugsatfda_docs/nda/2011/022119Orig1s001.pdf
Developed by the SNMMI PET Center of Excellence and the Center for Molecular Imaging Innovation & Translation
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NH3
[13N]ammonia
Fiecter M. Diagnostic Value of 13N-Ammonia Myocardial Perfusion PET: Added Value of Myocardial Flow
Reserve. J Nucl Med 2012; 53:1230-1234.
Herzog, BA et al. Long-Term Prognostic Value of 13N-Ammonia for Myocardial Perfusion Positron
Emission Tomography. JACC 2009; 54:150-156.
International Commission on Radiological Protection (ICRP) Task Group Committees 2 and 3. Radiation
Dose to Patients from Radiopharmaceuticals. ICRP Publication 53 and Addendum 1. Pages 61-62.
Pergamon Press. New York, NY. 1994. (Also referenced as ICRP Vol 18 (1-4))
Khademi S et al. Mechanism of Ammonia Transport by Amt/MEP/Rh: Structure of AmtB at 1.35 Å.
Science 2004; 305:1587-1594.
Murthy VL et al. Association between Coronary Vascular Dysfunction and Cardiac Mortality in Patients
with and without Diabetes Mellitus. Circulation 2012a; 121:1801-1811.
Murthy VL et al. Non-invasive quantification of coronary vascular dysfunction for diagnosis and
management of coronary artery disease. J Nucl Cardiol 2012; 19:1060-1072.
Saraste A. PET: Is myocardial flow quantification a clinical reality? J Nucl Cardiol 2012; 19:1044-1059.
SNMMI would like to acknowledge Jeanne Link, PhD for her contributions to developing this content.
Developed by the SNMMI PET Center of Excellence and the Center for Molecular Imaging Innovation & Translation
December 2012 - 5