Comparison of two synthetic methods to obtain [¹⁸F] N‐(2‐aminoethyl)‐5‐fluoropyridine‐2‐carboxamide, a potential MAO‐B imaging tracer for PET

Abstract

summaryThe compound Ro 19-6327, N-(2-arninoethyl)-5-chloropyridine-2-carboxmide, is known to inhibit reversibly and site specifically the enzyme monoamine oxidase B (MAO-B). The 1231-labelled iodo-analogue N-(2-aminoethyl)-5-iodopyridine-2-carboxamide (Ro 43-0463) was investigated successfully in human volunteers by means of SPET (Single Photon Emission Tomography). We developed therefore the synthesis and radiolabelling of the corresponding fluoro-analogue N-(2-aminoethyl)-5-fluoropyridine-2-carboxamide with ISF in order to carry out PET (Positron Emission Tomography) investigations of MAO-B related neuropsychiatric diseases. For this purpose two synthetic approaches leading to the electrophilic and the nucleophilic methods of ' SF radiolabelling were undertaken. The nucleophilic approach appeared to be superior when factors such as precursor synthesis, beam time, specific activity and radiochemical purity of the product are considered.

Synthesis of 11C, 18F, 15O, and 13N Radiolabels for Positron Emission Tomography

“…[203] Substitution at the meta position is possible if electron-withdrawing substituents are present at the ortho or para positions to activate the meta leaving groups. [204] Heteroaromatic nucleophilic 18 F-substitution reactions at the ortho position of the pyridyl groups is the most efficient route to 18 F-labeled fluoropyridyl derivatives when using [ 18 F]KF·K 222 . Additional activating groups, which are required for homoaromatic compounds, are not usually required for nucleophilic 18 F substitution of pyridyl groups at the ortho or para positions, the only requirement is to have a good leaving group.…”

Synthese von 11C‐, 18F‐, 15O‐ und 13N‐Radiotracern für die Positronenemissionstomographie

“…Eine kürzlich veröffentlichte Studie [197] vergleicht gebräuchliche Methoden für die einstufige Synthese von 1-Brom- [203] Eine meta-Substitution ist möglich, wenn elektronenziehende Substituenten in ortho-oder para-Stellung vorliegen und die meta-Abgangsgruppe aktivieren. [204] Heteroaromatische nucleophile 18 FSubstitutionen an der ortho-Position zur Pyridylgruppe sind die effizienteste Route zu 18 F-markierten Fluorpyridylen mit […”

An efficient new method for the synthesis of 3‐[18F]fluoro‐4‐aminopyridine via Yamada‐Curtius rearrangement

“…The nitrogen atom of the pyridine lowers the aromatic stability and stabilizes the intermediate Meisenheimer complex by both inductive and mesomeric effects . However, substitution at meta position remains challenging, often requiring an electron‐withdrawing group at ortho and/or para to the leaving group for successful fluorination …”