Nitrogen-13 Ammonia Radiopharmaceutical

Summary / Explanation

Introduction 

Nitrogen-13 ammonia, also known as ammonia N-13 or N-13 ammonia, is a diagnostic radiotracer most commonly used for cardiac and cerebral scintigraphy in positron emission tomography (PET) imaging. The short half-life of N13-ammonia necessitates onsite production of the isotope by a super-conducting compact cyclotron production system to generate an in-target purified isotope.[1]

FDA-Approved Indications

N-13 ammonia is an injectable FDA-approved tracer for myocardial perfusion evaluation at rest and stress tests in patients with existing or suspected coronary artery disease. A PET scan performed with N-13 ammonia has better sensitivity, specificity, and spatial contrast resolution than single photon emission computed tomography images, leading to the early detection of subclinical coronary artery disease.[2]

Off-Label Indications

The primary off-label indications for N-13 ammonia include the following oncologic uses:

• Differentiation of high-grade and low-grade gliomas [3]
• Differentiation of nonneoplastic brain lesions and glioma [4]
• Combination of N-13 ammonia and fluorodeoxyglucose F18, advantageous in defining cerebral lesions (eg, meningioma, cerebral lymphoma, and glioma) [5]
• Liver and prostate cancer diagnosis (in limited studies, potential initial beneficial findings observed) [6]

Mechanism of Action

N-13 ammonia injection serves as a radiotracer analog of ammonia. Following intravenous administration, the coronary capillaries within the myocardium demonstrate a high extraction rate, and N-13 ammonia undergoes rapid metabolic conversion to N-13 glutamine, leading to intracellular retention within myocardial cells. This selective accumulation of N-13 radiotracer enables PET visualization of the myocardium.

Pharmacokinetics

The following pharmacokinetic features characterize N-13 ammonia:

• Absorption: N-13 ammonia is administered intravenously as a bolus dose. The short half-life (t1/2 of 9.97 minutes) of N-13 ammonia provides an additional value of repeating the PET image for the same individual in a short period.[7]
• Distribution: Following intravenous administration, N-13 ammonia is distributed in different body organs, including the heart, liver, brain, bladder, and musculoskeletal system, in various concentrations depending on the blood flow and viable tissue retention of the isotope.[8]
• Metabolism: The drug is metabolized hepatically into 3 different metabolites—N-13 urea, the primary circulating metabolite, N-13 glutamine, and N13-glutamate.[9]
• Elimination: N13-urea metabolites are eliminated renally and excreted in the urine. Encouraging patient hydration and voiding immediately after the scan can minimize radiation exposure and increase renal excretion.[8]

Administration

Preprocedural hydration is crucial to optimize renal clearance of the radiotracer and minimize bladder wall radiation exposure. Before their PET study, patients should be instructed to remain well-hydrated by drinking plenty of fluids during the 4 hours. After the PET scan is completed, patients should be advised to urinate following each imaging session and to continue doing so as frequently as possible for 1 hour after scan completion.

Dosage and Strength

The recommended dose range of N13-ammonia intravenous injection is between 10 to 20 mCi (0.368 to 0.736 GBq).[10] N13-ammonia is available in the following strengths:

• Glass vial (30 mL) containing 0.138 to 1.387 GBq (3.75 to 37.5 mCi/mL) of ammonia N-13 injection in aqueous 0.9% sodium chloride solution

• Glass vial (30 mL) containing 0.14 to 9.62 GBq (3.75 to 260 mCi/mL) of ammonia N-13 injection

• Glass vial (30 or 50 mL) or syringe (3 or 5 mL) containing 0.138 to 9.62 GBq (3.75 to 260 mCi/mL) of ammonia N-13 injection

Storage Conditions

N13-ammonia should be stored upright in a shielded container at 77 °F (25 °C), room temperature.

Imaging Procedures

Rest imaging study

Withdraw N13-ammonia aseptically and administer 10 to 20 mCi as a bolus in a large peripheral vein. N13-ammonia exhibits a rapid onset of action; images can be obtained immediately following the IV bolus injection for 10 minutes with 16 frames for every cardiac cycle.

Stress imaging study

To perform a pharmacological stress test, administer a second dose of N 13-ammonia 3 minutes after starting the adenosine infusion (adenosine 0.12 mg/kg/min for 6 min). Separation between the procedures by 40 to 50 minutes is recommended to enable the decaying of the initial dose.[11] According to the Society of Nuclear Medicine and Molecular Imaging guidelines, careful examination of the images for any cardiac displacement between rest and stress phases is essential. In N-13 ammonia perfusion images, healthy individuals may show reduced radiotracer activity in the lateral wall of the left ventricle. This variation should be taken into account when interpreting patient images.[12] The European Association of Nuclear Medicine guidelines note that N-13 ammonia is effective for evaluating relative myocardial uptake and has shown greater sensitivity and specificity than single photon emission computed tomography myocardial perfusion imaging. Additionally, N-13 ammonia is highly valuable for precisely measuring myocardial blood flow.[13] Current PET myocardial perfusion imaging (MPI) practices using retention tracers like N-13 ammonia can introduce errors due to motion artifacts, particularly myocardial creep. Myocardial creep occurs when the heart subtly shifts position during imaging, especially under stress conditions. This movement can occur between acquiring early dynamic images to assess blood flow and later high-uptake images to define the region of interest and background activity. As a result, the region of interest defined on later images might not accurately reflect the true tracer distribution during the initial injection, leading to inaccurate blood flow measurements. A study assessed adenosine's impact on aligning attenuation correction maps from magnetic resonance and PET datasets during MPI on a hybrid PET/magnetic resonance scanner. The results showed frequent magnetic resonance attenuation correction and PET dataset misalignment during adenosine stress MPI. Myocardial creep may significantly contribute to this issue, stressing the need for careful data review and correction.[14][15]

Considerations in Special Populations

Hepatically impaired patients: Hepatomegaly and severe hepatic impairment increase the amount of drug trapped in the liver and decrease the amount of drug excreted.[8] However, the product labeling for N-13 ammonia does not include any dosage adjustment.

Renally impaired patients: A PET scan with N13-ammonia exhibits no renal adverse effects and provides a significant benefit in diagnosing patients with renal insufficiency.[16]

Pregnancy: Guidelines and expert opinion recommend against the use of a radioactive N13-ammonia agent during pregnancy due to fetal absorption of radiation during exposure to PET-CT imaging unless the benefit outweighs the risk, as is the case in some cancer diagnoses. Obtaining a PET scan in these situations is sometimes needed to determine the staging and treatment planning to improve patient outcomes.[17]

Breastfeeding: The recorded database regarding the use of N13-ammonia diagnostic agents for lactating mothers concluded that interruption of breastfeeding after administering the diagnostic isotope is unnecessary. However, the manufacturer recommends withholding breastfeeding for 2 hours after the tracer administration; therefore, to be prudent, nursing mothers can pump or express milk before the scan and store the milk for feeding in the 2 hours following the scan.[18][19]

Pediatric patients: N13-ammonia is not FDA-approved for use in pediatric patients. However, the N13-ammonia PET scan is a clinical decision-making technique used safely and effectively in diagnosing children with underlying coronary artery disease and imaging Williams syndrome infants with congenital heart diseases and can also provide supplemental perfusion information.[20]

Adverse Effects and Contraindications

Unlike traditional drugs, radiopharmaceutical adverse reactions are unusual. This could be due to the limited number of administrations and the fact that the pharmacological effect of these drugs is not dose-dependent. Based on a review of published literature, no adverse effects or specific contraindications for N13-ammonia have been reported.[21] The interactions of N13-ammonia injection with other drugs have not been studied for patients undergoing PET imaging.

Warnings

Given the potential cancer risk, the smallest effective dose of N13-ammonia should be used, and safe handling protocols must be followed to protect both patients and healthcare workers.

Enhancing Healthcare Team Outcomes

Radiation exposure can be hazardous to healthcare teams, the public, and the environment, particularly in nuclear medicine departments with significant workloads. Since patients are inevitable sources of radiation, this situation puts extra pressure on the healthcare team to balance patients' radiation safety and healthcare ethics. Effective communication with the patients, a good explanation of the test procedure, and a description of radiation safety basic principles, distance, and shielding before the isotope administration are all required to accomplish the as low as reasonably achievable (ALARA)' protocol in practice for saving time and minimizing the radiation exposure.

The Atomic Energy Regulatory Board is the regulating authority that provides radiation installation and farmwork guidelines at nuclear medicine departments; the hospital's radiation safety committee is responsible for implementing radiation safety measures and ensuring the equipment quality assurance status.[22] The radiation safety officer in charge follows the specific instructions of the radiation safety committee and implements the guidelines in different hospital radiation departments. Only qualified healthcare clinicians or regular staff with previous training in the basic principle of radiation safety are allowed to work in the radiation department; the radiation safety committee regulates this process along with the monthly alternate rotation of healthcare teams in the different nuclear and radiological departments.[23] An interprofessional team approach and communication between radiation oncologists, pharmacists, radiology technologists, and nurses is essential for optimizing patient outcomes with N13-ammonia.