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Nitrogen-13
Nitrogen-13
Nitrogen-13
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Nitrogen-13
General
Symbol13N
Namesnitrogen-13
Protons (Z)7
Neutrons (N)6
Nuclide data
Half-life (t1/2)9.965 min[1]
Parent isotopes13O (β+)
Decay modes
Decay modeDecay energy (MeV)
Electron capture2.220[2]
β+1.198[3]
Isotopes of nitrogen
Complete table of nuclides

Nitrogen-13 (13N) is a radioisotope of nitrogen used in positron emission tomography (PET). It has a half-life of a little under ten minutes, so it must be made at the PET site. A cyclotron may be used for this purpose.

Nitrogen-13 is used to tag ammonia molecules for PET myocardial perfusion imaging.

Production

[edit]

Nitrogen-13 is used in medical PET imaging in the form of 13N-labelled ammonia. It can be produced with a medical cyclotron, using a target of pure water with a trace amount of ethanol. The reactants are oxygen-16 (present as H2O) and a proton, and the products are nitrogen-13 and an alpha particle (helium-4).

1H + 16O → 13N + 4He

The proton must be accelerated to have total energy greater than 5.66 MeV. This is the threshold energy for this reaction,[4] as it is endothermic (i.e., the mass of the products is greater than the reactants, so energy needs to be supplied which is converted to mass). For this reason, the proton needs to carry extra energy to induce the nuclear reaction. Although the energy difference is actually 5.22 MeV, but if the proton only supplied this energy, the reactants would be formed with no kinetic energy; the requirement of momentum conservation imposes the higher energy threshold.

The presence of ethanol (at a concentration of ~5mM) in aqueous solution allows the convenient formation of ammonia as nitrogen-13 is produced. Other routes of producing 13N-labelled ammonia exist, some of which facilitate co-generation of other light radionuclides for diagnostic imaging.[5][6]

The N-13 role in the CNO cycle.

Nitrogen-13 plays a significant role in the CNO cycle, which is the dominant source of energy in main-sequence stars more massive than 1.5 times the mass of the Sun.[7]

Lightning may have a role in the production of nitrogen-13.[8][9]

[edit]

References

[edit]
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Nitrogen-13

View on Grokipedia
from Grokipedia
Nitrogen-13 (¹³N) is a short-lived radioactive of nitrogen with an of 13, consisting of 7 protons and 6 neutrons, that decays primarily by to stable carbon-13. It has a physical of 9.96 minutes, during which it emits positrons with a maximum of approximately 1.19 MeV, leading to the production of 511 keV annihilation photons suitable for detection in (PET) imaging. Due to its brief , ¹³N must be produced on-site at facilities equipped with cyclotrons, typically via the ¹⁶O(p,α)¹³N by bombarding enriched or oxygen targets with protons of 10–18 MeV . The isotope's primary application is in as a radiotracer, most notably in the form of [¹³N]ammonia for assessing myocardial in PET scans, enabling the diagnosis of and evaluation of cardiac blood flow. This use leverages ¹³N's rapid uptake and clearance in tissues, allowing for high-resolution with minimal radiation dose to patients, though the short necessitates precise timing in synthesis, , and administration. Beyond , ¹³N has been employed in for studying nitrogen in and soils, as well as in for , though clinical adoption remains limited outside cardiac applications due to production challenges. Ongoing advancements in technology and automated synthesis modules continue to improve the yield and purity of ¹³N , enhancing their for routine medical use.

Properties

Nuclear characteristics

Nitrogen-13 (¹³N) is a radioactive of , characterized by an of 7 and a of 13, which means it consists of 7 protons and 6 neutrons in its nucleus. The of ¹³N is 13.005739 u. This isotope exhibits a nuclear spin of 12−\frac{1}{2}^{-}, indicating a half-integer spin with negative parity. As an unstable , ¹³N has zero natural abundance in the . The of ¹³N is 9.965 ± 0.004 minutes, reflecting its short-lived nature. The corresponding decay constant λ\lambda is given by λ=ln⁡2T1/2≈0.0696\lambda = \frac{\ln 2}{T_{1/2}} \approx 0.0696 min⁻¹, where T1/2T_{1/2} is the .

Radioactive decay

Nitrogen-13 undergoes radioactive decay exclusively through (β⁺ decay) and (ε), with the primary mode being β⁺ decay accounting for nearly 100% of the decays. The decay proceeds to the stable ground state of , with a branching ratio of 99.803% for β⁺ and a negligible 0.197% for . The decay process can be represented by the equation: 13N→13C+e++νe^{13}\text{N} \to ^{13}\text{C} + e^{+} + \nu_e where the Q-value for the transition is 2.220 MeV. In β⁺ decay, the has a maximum of 1.198 MeV and an average energy of 492 keV. The emitted subsequently annihilates with an , producing two 511 keV gamma photons via .

Production

Cyclotron methods

Nitrogen-13 is primarily produced in via the proton-induced on , denoted as 16O(p,α)13N^{16}\mathrm{O}(p,\alpha)^{13}\mathrm{N}. This reaction utilizes protons accelerated to energies of 11-18 MeV, which is achievable with standard medical such as the or HM-18 models. The process involves bombarding a target containing , where the incident proton interacts with the nucleus, ejecting an and forming the nitrogen-13 isotope. This method is favored for its simplicity and high yield compared to alternatives, enabling on-site production due to the isotope's short of approximately 10 minutes. The target is typically enriched (H216O\mathrm{H_2^{16}O}), circulated through a flow chamber to manage heat from the beam, often with a trace amount of (about 10 mM) added as a chemical to promote the in-target formation of [13N]NH3[^{13}\mathrm{N}]\mathrm{NH_3}. Production yields from this reaction can reach saturation activities of up to ~30 mCi/μA·h at the end of bombardment, depending on the proton energy and target ; typical batch activities for 18 MeV protons on a 10 mL target are around 500-800 mCi for irradiation times of 20-40 minutes at beam currents of 10-50 μA. Medical cyclotrons equipped with beam currents of 10-50 μA are suitable, allowing batches sufficient for clinical positron emission tomography (PET) imaging, such as 500-800 mCi per run. Alternative nuclear reactions for nitrogen-13 production include 13C(p,n)13N^{13}\mathrm{C}(p,n)^{13}\mathrm{N}, which employs proton bombardment of enriched like or and is advantageous for lower-energy cyclotrons (around 7-10 MeV) in preclinical settings, though it yields lower activities (e.g., ~60 MBq/μA·h) and requires more complex handling. Another less common route is 10B(3He,n)13N^{10}\mathrm{B}(^{3}\mathrm{He},n)^{13}\mathrm{N}, using a beam on boron-10 , which provides modest yields (e.g., 63 MBq per kμA·h) but is rarely used due to the scarcity of suitable accelerators and . Historically, nitrogen-13 was first synthesized in 1934 by Joliot and through alpha irradiation of , but cyclotron-based production via proton reactions became routine in the 1970s with the advent of PET applications.

Post-irradiation processing

Following cyclotron irradiation of an aqueous target via the ¹⁶O(p,α)¹³N reaction, the target solution containing ¹³N primarily as (¹³NO₂⁻) and (¹³NO₃⁻) anions is transferred under overpressure or vacuum to an automated synthesis module for rapid processing. This step minimizes decay losses given the 9.97-minute of ¹³N. Target processing typically involves passing the solution through an anion-exchange resin, such as a QMA light cartridge, to remove anionic impurities like ¹⁸F-fluoride and metal ions, followed by trapping on a cation-exchange column (e.g., Accel CM or Sep-Pak CM) where the cationic ¹³NH₄⁺ species is retained after reduction. Ion-exchange is the standard method, preferred over older techniques for its efficiency and avoidance of volatile losses, achieving separation of ¹³N from target-derived ¹⁶O and radiolytic byproducts. The synthesis of [¹³N]NH₃ proceeds by reducing the anionic ¹³N species to ammonium ions (¹³NH₄⁺) either chemically (e.g., with in acidic solution) or via in-target facilitated by as a , followed by from the cation-exchange with sterile saline to yield neutral [¹³N]NH₃. This reaction in basic or neutral conditions ensures >95% radiochemical purity, with the product filtered aseptically through a 0.22 μm membrane and diluted to a final volume of 5–10 mL in 0.9% NaCl for injection. Automated modules, such as the Sumitomo radiosynthesizer or modified GE Tracerlab FXFDG, handle the entire process in 5–10 minutes from end-of-bombardment, incorporating software-controlled valves and pumps to ensure reproducibility and GMP compliance. These systems are essential for clinical throughput, enabling multiple doses per run. Quality control verifies product suitability through high-performance liquid chromatography (HPLC) or radio-thin-layer chromatography (radio-TLC) to confirm radiochemical purity (>95–99%), (no carrier added, >10¹¹ Bq/μmol), and absence of ¹⁸F contaminants (<0.1%). Additional tests include pH (4.5–8.0), visual clarity, radionuclide purity (>99.5% ¹³N via at 511 keV), sterility (14-day culture), and endotoxin levels (<175 EU per dose per USP <85>). Overall yield efficiency from beam-on to end-of-synthesis ranges from 50–70% (non-decay corrected), with typical activities of 2–30 GBq per batch depending on irradiation duration and beam current.

Applications

Positron emission tomography

(PET) utilizes the positrons emitted during the decay of nitrogen-13 (¹³N) to generate high-resolution images of physiological processes. Upon emission, the positron travels a short distance (typically 1-2 mm in tissue) before annihilating with an , producing two gamma photons each with an energy of 511 keV that travel in nearly opposite directions. These photons are detected simultaneously (in coincidence) by a ring of scintillation detectors surrounding the patient, enabling the reconstruction of three-dimensional images that localize the site of ¹³N decay with millimeter precision. The short physical of ¹³N, approximately 9.97 minutes, allows for multiple serial scans in a single session with reduced burden to the patient, facilitating dynamic studies of tracer kinetics. Additionally, the relatively low of the emitted positrons results in a short range (mean approximately 1.2 mm), contributing to superior compared to isotopes with higher-energy positrons. This combination makes ¹³N particularly advantageous for applications requiring high temporal resolution and repeated imaging. The most common radiotracer incorporating ¹³N is [¹³N]NH₃ (), prepared by proton of enriched targets followed by chemical processing to yield the form suitable for intravenous injection. This tracer is avidly taken up by tissues in proportion to blood flow, enabling quantitative assessment of . In typical PET protocols, an injection dose of 370-740 MBq (10-20 mCi) of [¹³N]NH₃ is administered, with image acquisition commencing 5-10 minutes post-injection to allow for blood clearance, followed by 5-10 minutes of static or dynamic scanning. Compared to oxygen-15 (¹⁵O), which has a much shorter of about 2 minutes, ¹³N offers greater logistical flexibility for tracer distribution and imaging timing while maintaining suitability for ammonia-based labeling in studies. Although ¹⁵O enables ultra-rapid kinetics, the longer of ¹³N reduces the need for on-site production immediacy and supports more straightforward clinical workflows.

Myocardial and metabolic imaging

Nitrogen-13 tracers, particularly [¹³N]ammonia, are widely used in (PET) for to evaluate (CAD), myocardial viability, and coronary flow reserve. In rest or stress conditions, [¹³N]ammonia uptake reflects myocardial blood flow, with high extraction efficiency allowing quantitative assessment of perfusion defects indicative of ischemia or . Studies have demonstrated sensitivities exceeding 90% for detecting CAD, such as 93% in exercise PET protocols without myocardial and up to 98% in broader patient cohorts. For viability assessment, late-phase [¹³N]ammonia retention correlates with preserved metabolic function in dysfunctional myocardium, aiding differentiation from . Additionally, dynamic enables calculation of myocardial flow reserve (MFR), typically expressed as the ratio of stress to rest flow, providing prognostic insights into microvascular dysfunction even in non-obstructive CAD. N 13 Injection received FDA approval in 2007 specifically for diagnostic PET of the myocardium under rest or pharmacologic stress to guide CAD management. In metabolic imaging, [¹³N]ammonia serves as a tracer to monitor incorporation into key biochemical pathways, including and protein synthesis as well as and cycles. Upon administration, [¹³N]ammonia rapidly integrates into and via glutaminases and , facilitating tracking of flux in hepatic and renal . This enables evaluation of efficiency and synthesis, which are critical in conditions like liver dysfunction or . For instance, studies in liver have shown rapid exchange of [¹³N] among aminotransferase reactions, highlighting its utility in quantifying assimilation for biosynthetic processes. Beyond human applications, [¹³N]ammonia has been used in to study in and soils. Such applications provide insights into without the confounding effects of longer-lived isotopes. Beyond , Nitrogen-13 tracers show potential in oncologic imaging, particularly for and . In , [¹³N]ammonia PET/CT exhibits high accuracy for detecting recurrence, outperforming contrast-enhanced MRI, especially in low-grade tumors where it identifies expression linked to tumor proliferation. For , [¹³N] uptake correlates with metabolism in primary lesions and metastases, complementing [¹⁸F]FDG for staging and complementing hypoxia assessment in aggressive phenotypes. These applications leverage the tracer's affinity for pathways upregulated in hypoxic tumor microenvironments, though clinical adoption remains investigational. Clinically, [¹³N] PET outperforms (SPECT) for ischemia detection, achieving up to 85% accuracy versus 77% for SPECT, with quantitative myocardial blood flow measurements in ml/min/g enabling precise risk stratification and reduced radiation exposure.

Safety and handling

Radiation protection

Radiation protection for Nitrogen-13, a positron-emitting radioisotope with a of approximately 10 minutes, primarily addresses the hazards posed by the 511 keV gamma rays resulting from positron-electron following its decay. Shielding protocols typically employ dense materials such as lead or , with thicknesses of 4-10 cm in hot cells to attenuate these high-energy photons effectively, ensuring that manipulations occur behind barriers that reduce exposure to background levels. shields and containers often use 1-2 cm of lead equivalent for routine handling, balancing protection with practicality given the isotope's short decay time. The ALARA (As Low As Reasonably Achievable) principle guides all handling procedures, emphasizing minimization of exposure through reduced time, increased distance, and optimized shielding, which is particularly feasible due to Nitrogen-13's brief that limits cumulative dose accumulation. Operators wear , including waterproof gloves and dosimeters, and perform tasks swiftly in shielded environments to keep occupational doses well below regulatory limits, often achieving annual exposures under 1 mSv for routine staff. Production and dispensing facilities incorporate cyclotron vaults with thick concrete shielding (typically 1-2 m) to contain neutron and gamma radiation during bombardment, while radiopharmacy areas feature hot cells and L-block workstations under negative pressure ventilation systems to prevent airborne release of volatile compounds like ammonia. These setups maintain air flow rates of 10-30 air changes per hour, with HEPA filtration exhausting to restricted areas, ensuring containment of any aerosolized activity. Waste management relies on decay-in-storage, where contaminated materials such as vials, syringes, and wipes are held in designated shielded containers for at least 10 half-lives (about 100 minutes), after which activity falls below exempt quantities and can be disposed of as non-radioactive waste per regulatory approval. This approach avoids complex processing for short-lived isotopes, with storage areas monitored by survey meters to confirm decay prior to release. Regulatory standards from the (IAEA) and the U.S. (NRC) mandate these protocols, including compliance with IAEA Safety Standards Series No. GSR Part 3 for medical and NRC 10 CFR Part 20 for occupational dose limits, ensuring safe handling of PET isotopes like Nitrogen-13 across production, use, and disposal.

Dosimetry and biodistribution

The dosimetry of Nitrogen-13-labeled ammonia ([¹³N]NH₃) in (PET) imaging is characterized by relatively low to patients due to its short physical of approximately 9.97 minutes. The effective dose from a typical administered activity of 740 MBq is estimated at 1.5–2.0 mSv, based on biokinetic models developed by the (ICRP). This value aligns with calculations using ICRP Publication 53, which reports an effective dose coefficient of 0.0022 mSv/MBq for adults, reflecting the rapid decay and clearance of the tracer that minimizes prolonged internal exposure. Organ-absorbed doses vary by tissue, with the highest values observed in structures exhibiting significant uptake. The urinary bladder wall receives the highest dose at approximately 0.014–0.02 mGy/MBq, attributable to accumulation from urinary , while the heart wall experiences around 0.007–0.01 mGy/MBq due to myocardial extraction. Other organs such as the kidneys (∼0.006 mGy/MBq) and liver also receive notable doses from initial uptake and clearance pathways. Biodistribution of [¹³N]NH₃ following intravenous injection demonstrates rapid clearance from the , with a plasma of about 1 minute and no significant occurring before . Approximately 80% of the tracer is extracted by the myocardium within 2 minutes post-injection, peaking at 1.5% of the injected dose per gram of myocardial tissue, while the remainder distributes to the liver, , kidneys, and salivary glands. Hepatic uptake facilitates clearance, with about 50% of the activity excreted via within 10 minutes, primarily as unchanged , resulting in low retention in non-target organs. The stochastic risk from [¹³N]NH₃ PET scans is minimal, with an estimated cancer induction probability of less than 0.01% per procedure, largely mitigated by the tracer's brief that limits cumulative exposure compared to longer-lived isotopes. This low risk profile supports its routine use in while adhering to ALARA (as low as reasonably achievable) principles.

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