Nitrogen‐13: historical review and future perspectives

Abstract

Positron emission tomography is an ultra-sensitive, in vivo molecular imaging technique that allows the determination of the spatiotemporal distribution of a positron emitter labeled radiotracer after administration into living organisms. Among all existing positron emitters, (18) F has been by far the most widely used both in clinical diagnosis and in preclinical investigation, while the use of (11) C significantly increased after the 1980s because of the widespread installation of biomedical cyclotrons. The use of other shorter-lived positron emitters such as (13) N (T1/2 = 9.97 min) has been historically more restricted. Paradoxically, its stable isotope ((14) N) is present in many biological active molecules; consequently, the development of strategies for the efficient incorporation of (13) N into radiotracers would represent an interesting alternative to (11) C- and (18) F-labeling. In the current paper, the developments related to (13) N chemistry are reviewed, including different production routes of primary precursors and their applications to the preparation of more complex (13) N-labeled molecules. The current situation and future perspectives are also briefly discussed.

Chemistry for Positron Emission Tomography: Recent Advances in 11C‐, 18F‐, 13N‐, and 15O‐Labeling Reactions

“…[211] [ 13 N]NH 3 ,w idely used in clinical PET imaging for cardiovascular diseases [212] and glutamate metabolism, [213] was produced by proton irradiation of water. [211] [ 13 N]NH 3 could also serve as ab uilding block for 13 N transformations,i ncluding enzymatic reactions,H ofmann rearrangements,a mide or imine reduction, amination of organoboranes,substitutions,and amidations.These reactions were used to prepare 13 N-labeled amino acids,p rimary amines,a mides,u reas,c arbamates,a nd metal complexes (Scheme 37 B). [211,[214][215][216] [ 13 N]NO 2 À is another commonly used synthon for 13 N chemistry,w hich can be prepared by proton irradiation of water, oxidation of [ 13 N]NH 3 using gallium or cobalt oxides,or reduction of [ 13 N]NO 3 À by metals or eukaryotic nitrate reductase (Scheme 37 A).…”

“…[211,[214][215][216] [ 13 N]NO 2 À is another commonly used synthon for 13 N chemistry,w hich can be prepared by proton irradiation of water, oxidation of [ 13 N]NH 3 using gallium or cobalt oxides,or reduction of [ 13 N]NO 3 À by metals or eukaryotic nitrate reductase (Scheme 37 A). [211,217,218] The 13 N-nitrosation of ureas,s econdary amines,a nd thiols could be realized with [ 13 N]NO 2 À . [217,219] Forexample,GSNO,amost widely studied S-nitrosothiol, was synthesized in 24 %RCY.…”

Labelling with positron emitters of pnicogens and chalcogens

“…Nitrogen‐13 and phosphorus‐30 ( 30 P), both nuclides of the important endogenous elements of the pnicogen group of the periodic table, are pure positron emitters (cf Table ). Nitrogen‐13 is an important nuclide for PET, and several chemical transformation reactions were examined despite its short half‐life of 9.97 minutes …”

“…The positron emitters nitrogen‐13 ( 13 N) and oxygen‐15 ( 15 O) are important for labelling since their stable isotopes (nitrogen‐14 and oxygen‐16) are ubiquitous in endogenous compounds or in other biologically active organic molecules . However, the relatively short half‐lives of both nuclides, which are much shorter than the half‐lives of the commonly used positron‐emitting nuclides carbon‐11 ( 11 C; t 1/2 = 20 min) and fluorine‐18 ( 18 F; t 1/2 = 109.7 min), limit their broad application in PET, requiring preparation of single‐dose batches and necessitating the development of efficient synthetic strategies …”

Biocatalysis in radiochemistry: Enzymatic incorporation of PET radionuclides into molecules of biomedical interest

“…Fluorine‐18 and 11 C have been extensively used because of their relatively long half‐lives ( t 1/2 = 109.8 and 20.4 min, respectively) and versatile chemistries. The use of shorter lived positron emitters such as 13 N ( t 1/2 = 9.97 min) has been historically more restricted; in fact, synthetic strategies to incorporate 13 N into bioactive molecules are scarce …”