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| Home > Publications database > Development of $^{18}$F-labelled radioligands for molecular imaging of the dopamine D$_{4}$ receptor |
| Home > Publications database > Development of $^{18}$F-labelled radioligands for molecular imaging of the dopamine D$_{4}$ receptor |
| Dissertation / PhD Thesis/Book | PreJuSER-19134 |
2011
Forschungszentrum Jülich GmbH Zentralbibliothek, Verlag
Jülich
ISBN: 978-3-89336-738-2
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Please use a persistent id in citations: http://hdl.handle.net/2128/4513
Abstract: The five subtypes of the dopamine receptor play an important role in the human brain. The dopamine D$_{4}$ receptor is involved in processes of behaviour control and is assumed to be responsible for the emergence of the attention deficit hyperactivity disorder (ADHD) as well as psychotic diseases like schizophrenia. While most of the other dopamine receptors are well known there is a lack of suitable radioligands for the examination of the D$_{4}$ receptor by functional neuroimaging via positron emission tomography (PET). This is due to the extremely low distribution density of D$_{4}$ in the central nervous system. In this work the radiosynthesis of such D$_{4}$ ligands was developed and pharmacologically evaluated. Therefore, selected pharmaceutical lead structures were labelled via nucleophilic substitution with no-carrier-added (n.c.a.) [$^{18}$F]fluoride at an aromatic ring and subsequently coupled in a 1-2 step build-up reaction to the desired ligands. As first approach, an efficient radiosynthesis of the highly selective [$^{18}$F]FAUC 316 ligand ([$^{18}$F]1) was developed. Starting from $^{18}$F-labelling of the symmetric iodonium salts bis(4-bromophenyl)iodonium triflate and bis(4-iodophenyl)iodonium triflate the corresponding 4-[$^{18}$F]fluorohalobenzenes were obtained in radiochemical yields (RCY) of up to 60 %. Pd-catalyzed cross-coupling of the labelling products and piperazine with Pd$_{2}$(dba)$_{3}$ or Pd(OAc)$_{2}$ led to 4-[$^{18}$F]fluorophenylpiperazine in a RCY of up to 42 %. During the synthesis of standard and precursors 5-Cyanoindol-2-carbaldehyd was synthesized in four reaction steps with an overall yield of 15 % and coupled to [$^{18}$F]FAUC 316. The overall-RCY after high performance liquid chromatography (HPLC) separation was 10 %. [$^{18}$F]FAUC 316 was not suitable for further evaluation steps in vivo due to the very high nonspecific binding content determined by in vitro autoradiography. Alternatively, the radioligands 6-(4-[4-$^{18}$F]fluorobenzyl]piperazine-1-yl)benzodioxine ([$^{18}$F]$\textbf{33a}$), 6-(4-[4-[$^{18}$F]fluoro-(3-methoxybenzyl)] piperazine-1-yl)benzodioxine ([$^{18}$F]$\textbf{33b}$), 6-(4-[4-[$^{18}$F]fluoro-(3-hydroxybenzyl)]piperazine-1-yl)benzodioxine ([$^{18}$F]$\textbf{33d}$) und 6-(4-[6-[$^{18}$F]fluoropyridine-3-yl]piperazine-1-yl)benzodioxine ([$^{18}$F]$\textbf{33e}$) were synthesized as benzodioxine derivatives with decreasing lipophilicity. For this 1-(1,4-benzodioxine-6-yl)piperazine ($\textbf{30}$) was coupled with the corresponding aldehyde derivatives by a reductive amination reaction in overall-RCY of 35 %, 20 %, 9 % and 15 %, respectively. $\textit{In vitro}$ autoradiography on rat brain slices confirmed the correlation between non-specific binding and lipophilicity and lend [$^{18F}]\textbf{33d}$ and [$^{18F}]\textbf{33e}$ as putative radiotracers. Since [$^{18}F]\textbf{33e}$ showed better D$_{4}$ selectivity, $\textit{ex vivo}$ organ uptake, metabolization rate and brain distribution were determined. Examinations showed a principle qualification of [$^{18}F]\textit{33e}$ for the visualization of the D$_{4}$ receptors, but due to a lack of experiences a clear relation of D$_{4}$ to the ligand was not possible up to now. Further examinations in vivo are required to verify the ability of mapping D$_{4}$ receptors by this new radioligand.
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