%0 Journal Article
%T Ex Vivo Characterization of a Novel Iodine-123-Labelled Aminomethylchroman as a Potential Agonist Ligand for SPECT Imaging of Dopamine D2/3 Receptors
%A Jan-Peter van Wieringen
%A Kora de Bruin
%A Henk M. Janssen
%A P. Michel Fransen
%A Anton G. M. Janssen
%A Peter A. van Doremalen
%A Martin C. Michel
%A Philip H. Elsinga
%A Jan Booij
%J International Journal of Molecular Imaging
%D 2014
%I Hindawi Publishing Corporation
%R 10.1155/2014/507012
%X For imaging of dopamine D2/3 receptors, agonist tracers are favoured over antagonists because they are more sensitive to detection of dopamine release and because they may selectively label the high-affinity receptor state. We have developed novel D2/3 receptor selective agonists that can be radiolabelled with [123I], which label is advantageous over most other labels, such as carbon-11, as it has a longer half-life. Particularly, we considered (R) N-[7-hydroxychroman-2-yl]-methyl 4-iodobenzyl amine (compound 1) as an attractive candidate for development as it shows high binding affinity to D2/3 receptors in vitro, and here we report on the characterization of this first [123I]-labelled D2/3 receptor agonist radiopharmaceutical intended for SPECT imaging. The appropriate tin precursor for [123I]-1 was developed and was successfully radiolabelled with iodine-123 giving a moderate yield (30¨C35%) and a good purity (>95%) for [123I]-1. In biodistribution experiments in Wistar rats intravenous injection of [123I]-1 resulted in a fast brain uptake, where the observed binding in the D2/3 receptor-rich striatum was slightly higher than that in the cerebellum 30£¿min to 4£¿h p.i. Storage phosphor imaging experiments, however, did not show specific D2/3 receptor binding. In conclusion, despite promising in vitro data for 1, neither specific ex vivo binding nor high signal-to-noise ratios were found in rodents for [123I]-1. 1. Introduction A disturbed dopamine system plays a role in the etiology of several neuropsychiatric disorders, including Parkinson¡¯s disease (PD) [1], schizophrenia [2], and drug addiction [3]. The prevalence of PD and schizophrenia is about 1% [4], while the prevalence of addiction (including alcoholism) is much higher [5], leading to a large disease burden. Dopamine receptors are part of the superfamily of G-protein coupled receptors (GPCRs) and can, based on their action on adenylyl cyclase (AC), be divided into 2 subfamilies. After activation, the dopamine D1-like (D1 and D5) receptors stimulate AC to produce the second messenger cyclic adenosine monophosphate (cAMP) while the D2-like (D2, D3, and D4) receptors inhibit this enzyme [6, 7]. Like other GPCRs they demonstrate interconvertible high- and low-affinity states for agonists in vitro [8¨C11]. The D2/3 high-affinity state represents the active form of the receptor [12]. Changes in the density of D2/3 receptors in this high-affinity state seem to be more important for the pathophysiology of neuropsychiatric disorders than those of the total receptor density; in several animal models
%U http://www.hindawi.com/journals/ijmi/2014/507012/