Syntheses, in vitro evaluation and radioiodination of halogenated benzamide derivatives for the visualization of D2-like dopamine receptors with SPECT

Abstract

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Objectives: The benzamides [¹⁸F]fallypride ([¹⁸F]FP) and [¹⁸F]desmethoxyfallypride ([¹⁸F]DMFP) have found application as D2-selective PET-radioligands imaging dopamine receptors in the brain. For SPECT [¹²³I]IBZM is the most commonly applied radioligand. Employing the favourable properties of [¹⁸F]FP and [¹⁸F]DMFP and thereby offering an interesting alternative to IBZM two iodinated analogues of the fluorinated allylic derivatives, N-allylepidepride (NAE) and N-allyldesmethoxyepidepride (NADE), were synthesized. Syntheses of bromine and chlorine analogues were performed as well.

Methods: Precursors and reference compounds were synthesized by coupling the respective benzoic acid derivative with (S)-2-aminomethyl-1-allylpyrrolidine. The benzoic acid derivatives were synthesized by methylating and/or oxidizing the corresponding aldehydes or carboxylic acids. Chloro-ethylformiate was employed to activate the benzoic acid derivatives before reacting them with (S)-2-aminomethyl-1-allylpyrrolidine. To obtain the stannous precursors the reference compounds were reacted with hexabutyldistannane using tetrakis(triphenylphosphine)palladium(0) as catalyst. Lipophilicities were determined using the HPLC-method. Affinities of the synthesized benzamides to dopamine receptor subtypes as well as to serotonergic and adrenergic receptor subtypes were examined. Due to easier handling and longer half-life radioiodinations were carried out using [¹³¹I]NaI in a phosphate buffer system with chloroamine-T as oxidizing agent. Radioiodination experiments with [¹²³I]NaI were conducted as well.

Results: For the D2-receptor (hD2_short) k_i-values were 0.7 nM for NAE, 19 nM for NADE, 2.2 nM for FP and 30 nM for DMFP. LogD_7.4-values for NAE, NADE, FP and DMFP were determined as 2.81, 2.70, 2.66 and 2.63 respectively. Radiochemical yields for [¹³¹I]NAE and [¹³¹I]NADE were moderate to good. Autoradiography in rat brain showed excellent visualization of the dopamine receptor regions. Ex vivo biodistribution studies in Sprague Dawley rats with both radioiodinated compounds showed results in compliance with those obtained for studies with [¹⁸F]FP and [¹⁸F]DMFP.

Conclusions: The promising results of the in vitro studies for NAE and the new compound NADE as well as the brominated derivatives justify further investigations.