Labeling of benzodioxin piperazines with fluorine‐18 as prospective radioligands for selective imaging of dopamine D₄ receptors

Abstract

The D(4) receptor is of high interest for research and clinical application but puts high demands on appropriate radioligands to be useful tools for investigation. Search for adequate radioligands suitable for in vivo imaging is therefore still in progress. The potential neuroleptic drug 6-(4-[4-fluorobenzyl]piperazin-1-yl)benzodioxin shows high affinity and selectivity to the D(4) receptor. Derivatization of this lead structure by adding hydrophilic moieties was carried out in order to lower its lipophilicity what led to three new putative dopamine receptor D(4) ligands. A comprehensive description of the syntheses of standard compounds and corresponding labeling precursors is given which were obtained in satisfactory yields. Furthermore, the radiosyntheses by direct (18) F-labeling and build-up synthesis were compared. All derivatives of 6-(4-[4-fluorobenzyl]-piperazin-1-yl)benzodioxin were successfully synthesized in (18) F-labeled form with radiochemical yields of 9-35% and molar activities of 30-60 GBq/µmol using one-pot procedures.

Rapid synthesis of maleimide functionalized fluorine‐18 labeled prosthetic group using “radio‐fluorination on the Sep‐Pak” method

“…The same research group has demonstrated high radiochemical conversion using the pyridine derivative by halogen (Cl) exchange. 5 More challenging fluorine-18 labelings at the meta-position to prepare 3-[ 18 F]fluorobenzaldehydes have also been reported by our 7 and other groups from a variety of precursors. [8][9][10] Recently, Richarz et al reported fluorine-18 labeled benzaldehydes according to the "minimalist" radiolabeling protocol, without base and azeotropic drying of [ 18 F]fluoride.…”

“…A variety of prosthetic groups containing aldehyde functionalities have been developed . Kugler et al and Lemaire et al reported labeling of 4‐fluorobenzaldehydes and 2‐fluorobenzaldehydes and compared the radiolabeling efficiencies of nitro‐ and trimethylammonium triflate‐ precursors . Although conversions were comparable, the reaction was much faster for the trimethylammonium triflate precursors.…”

“…Moreover, purification of 2 or 4‐[ 18 F]fluorobenzaldehydes from the trimethylammonium triflate precursors was done simply by using a Sep‐Pak. The same research group has demonstrated high radiochemical conversion using the pyridine derivative by halogen (Cl) exchange . More challenging fluorine‐18 labelings at the meta‐position to prepare 3‐[ 18 F]fluorobenzaldehydes have also been reported by our and other groups from a variety of precursors .…”

“…3,4 Kugler et al and Lemaire et al reported labeling of 4-fluorobenzaldehydes and 2-fluorobenzaldehydes and compared the radiolabeling efficiencies of nitro-and trimethylammonium triflate-precursors. 5,6 Although conversions were comparable, the reaction was much faster for the trimethylammonium triflate precursors. Moreover, purification of 2 or 4-[ 18 F] fluorobenzaldehydes from the trimethylammonium triflate precursors was done simply by using a Sep-Pak.…”

Fluorine-18 labelled building blocks for PET tracer synthesis

“…A wellknown reaction for aldehydes is the aldol condensation, which has been used in the synthesis of PET tracers with the dibenzalacetone core structure, as can be seen in Section 3. 243,244 Comparable conversions were observed for both leaving groups, however reactions were in general faster for the trimethylammonium triflate containing precursors (5 minutes versus 15 minutes respectively).…”