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 (30–35%) 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 [8–11]. 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
References
[1]
J. Booij, G. Tissingh, A. Winogrodzka, and E. A. Van Royen, “Imaging of the dopaminergic neurotransmission system using single-photon emission tomography and positron emission tomography in patients with parkinsonism,” European Journal of Nuclear Medicine, vol. 26, no. 2, pp. 171–182, 1999.
[2]
S. Kapur and D. Mamo, “Half a century of antipsychotics and still a central role for dopamine D2 receptors,” Progress in Neuro-Psychopharmacology and Biological Psychiatry, vol. 27, no. 7, pp. 1081–1090, 2003.
[3]
N. D. Volkow, J. S. Fowler, G.-J. Wang, and J. M. Swanson, “Dopamine in drug abuse and addiction: results from imaging studies and treatment implications,” Molecular Psychiatry, vol. 9, no. 6, pp. 557–569, 2004.
[4]
S. von Campenhausen, B. Bornschein, R. Wick et al., “Prevalence and incidence of Parkinson's disease in Europe,” European Neuropsychopharmacology, vol. 15, no. 4, pp. 473–490, 2005.
[5]
R. B. Goldstein, D. A. Dawson, S. Patricia Chou, and B. F. Grant, “Sex differences in prevalence and comorbidity of alcohol and drug use disorders: results from wave 2 of the national epidemiologic survey on alcohol and related conditions,” Journal of Studies on Alcohol and Drugs, vol. 73, no. 6, pp. 938–950, 2012.
[6]
J. C. Stoof and J. W. Kebabian, “Opposing roles for D-1 and D-2 dopamine receptors in efflux of cyclic AMP from rat neostriatum,” Nature, vol. 294, no. 5839, pp. 366–368, 1981.
[7]
P. G. Strange, “New insights into dopamine receptors the central nervous system,” Neurochemistry International, vol. 22, no. 3, pp. 223–236, 1993.
[8]
D. R. Sibley, A. de Lean, and I. Creese, “Anterior pituitary dopamine receptors. Demonstration of interconvertible high and low affinity states of the D-2 dopamine receptor,” Journal of Biological Chemistry, vol. 257, no. 11, pp. 6351–6361, 1982.
[9]
C. L. Chio, M. E. Lajiness, and R. M. Huff, “Activation of heterologously expressed D3 dopamine receptors: comparison with D2 dopamine receptors,” Molecular Pharmacology, vol. 45, no. 1, pp. 51–60, 1994.
[10]
P. Seeman, D. Weinshenker, R. Quirion, et al., “Dopamine supersensitivity correlates with D2High states, implying many paths to psychosis,” Proceedings of the National Academy of Sciences of the United States of America, vol. 102, no. 9, pp. 3513–3518, 2005.
[11]
J.-P. Van Wieringen, J. Booij, V. Shalgunov, P. Elsinga, and M. C. Michel, “Agonist high- and low-affinity states of dopamine D2 receptors: methods of detection and clinical implications,” Naunyn-Schmiedeberg's Archives of Pharmacology, vol. 386, no. 2, pp. 135–154, 2013.
[12]
N. R. Zahniser and P. B. Molinoff, “Effect of guanine nucleotides on striatal dopamine receptors,” Nature, vol. 275, no. 5679, pp. 453–455, 1978.
[13]
P. Seeman, J. Schwarz, J.-F. Chen et al., “Psychosis pathways converge via D2High dopamine receptors,” Synapse, vol. 60, no. 4, pp. 319–346, 2006.
[14]
S. R. George, M. Watanabe, and P. Seeman, “Dopamine D2 receptors in the anterior pituitary: a single population without reciprocal antagonist/agonist states,” Journal of Neurochemistry, vol. 44, no. 4, pp. 1168–1177, 1985.
[15]
S. J. Finnema, B. Bang-Andersen, H. V. Wikstr？m, and C. Halldin, “Current state of agonist radioligands for imaging of brain dopamine D2/D3 receptors in vivo with positron emission tomography,” Current Topics in Medicinal Chemistry, vol. 10, no. 15, pp. 1477–1498, 2010.
[16]
N. Ginovart, M. Willeit, P. Rusjan, et al., “Positron emission tomography quantification of [11C]-(+)-PHNO binding in the human brain,” Journal of Cerebral Blood Flow & Metabolism, vol. 27, no. 4, pp. 857–871, 2007.
[17]
R. Narendran, W. G. Frankle, N. S. Mason et al., “Positron emission tomography imaging of D2/3 agonist binding in healthy human subjects with the radiotracer [11C]-N-propyl- norapomorphine: preliminary evaluation and reproducibility studies,” Synapse, vol. 63, no. 7, pp. 574–584, 2009.
[18]
T. Otsuka, H. Ito, C. Halldin et al., “Quantitative PET analysis of the dopamine D2 receptor agonist radioligand 11C-(R)-2-CH3O-N-n-propylnorapomorphine in the human brain,” Journal of Nuclear Medicine, vol. 50, no. 5, pp. 703–710, 2009.
[19]
R. Narendran, N. S. Mason, C. M. Laymon et al., “A comparative evaluation of the dopamine D2/3 agonist radiotracer [11C](-)-N-propyl-norapomorphine and antagonist [11C]raclopride to measure amphetamine-induced dopamine release in the human striatum,” Journal of Pharmacology and Experimental Therapeutics, vol. 333, no. 2, pp. 533–539, 2010.
[20]
P. Shotbolt, A. C. Tziortzi, G. E. Searle et al., “Within-subject comparison of [11C]-(+)-PHNO and [11C]raclopride sensitivity to acute amphetamine challenge in healthy humans,” Journal of Cerebral Blood Flow and Metabolism, vol. 32, no. 1, pp. 127–136, 2012.
[21]
R. Narendran, D.-R. Hwang, M. Slifstein, et al., “In vivo vulnerability to competition by endogenous dopamine: comparison of the D2 receptor agonist radiotracer (？)-N-[11C]propyl-norapomorphine ([11C]NPA) with the D2 receptor antagonist radiotracer [11C]-raclopride,” Synapse, vol. 52, no. 3, pp. 188–208, 2004.
[22]
N. Ginovart, L. Galineau, M. Willeit et al., “Binding characteristics and sensitivity to endogenous dopamine of [11C]-(+)-PHNO, a new agonist radiotracer for imaging the high-affinity state of D2 receptors in vivo using positron emission tomography,” Journal of Neurochemistry, vol. 97, no. 4, pp. 1089–1103, 2006.
[23]
S. J. Finnema, V. Stepanov, R. Nakao, et al., “18F-MCL-524, an 18F-labeled dopamine D2 and D3 receptor agonist sensitive to dopamine: a preliminary PET study,” Journal of Nuclear Medicine, vol. 55, no. 7, pp. 1164–1170, 2014.
[24]
J.-P. Van Wieringen, V. Shalgunov, H. M. Janssen et al., “Synthesis and characterization of a novel series of agonist compounds as potential radiopharmaceuticals for imaging dopamine D2/3 receptors in their high-affinity state,” Journal of Medicinal Chemistry, vol. 57, no. 2, pp. 391–410, 2014.
[25]
R. E. Mewshaw, J. Kavanagh, G. Stack et al., “New generation dopaminergic agents. 1. Discovery of a novel scaffold which embraces the D2 agonist pharmacophore. Structure-activity relationships of a series of 2-(aminomethyl)chromans,” Journal of Medicinal Chemistry, vol. 40, no. 26, pp. 4235–4256, 1997.
[26]
J. Booij, G. Andringa, L. J. M. Rijks, et al., “[123I]FP-CIT binds to the dopamine transporter as assessed by biodistribution studies in rats and SPECT studies in MPTP-lesioned monkeys,” Synapse, vol. 27, pp. 183–190, 1997.
[27]
B. Kiss, F. Horti, and A. Bobok, “In vitro and in vivo comparison of [3H](+)-PHNO and [3H]raclopride binding to rat striatum and lobes 9 and 10 of the cerebellum: a method to distinguish dopamine D3 from D2 receptor sites: a method to distinguish dopamine D3 from D2 receptor sites,” Synapse, vol. 65, no. 6, pp. 467–478, 2011.
[28]
R. J. J. Knol, K. de Bruin, J. de Jong, B. L. F. van Eck-Smit, and J. Booij, “In vitro and ex vivo storage phosphor imaging of short-living radioisotopes,” Journal of Neuroscience Methods, vol. 168, no. 2, pp. 341–357, 2008.
[29]
M. Laruelle, M. Slifstein, and Y. Huang, “Relationships between radiotracer properties and image quality in molecular imaging of the brain with positron emission tomography,” Molecular Imaging and Biology, vol. 5, no. 6, pp. 363–375, 2003.
[30]
D. F. Wong and M. G. Pomper, “Predicting the success of a radiopharmaceutical for in vivo imaging of central nervous system neuroreceptor systems,” Molecular Imaging and Biology, vol. 5, no. 6, pp. 350–362, 2003.
[31]
E. J. Cobos, E. D. Pozo, and J. M. Baeyens, “Irreversible blockade of sigma-1 receptors by haloperidol and its metabolites in guinea pig brain and SH-SY5Y human neuroblastoma cells,” Journal of Neurochemistry, vol. 102, no. 3, pp. 812–825, 2007.
[32]
W. K. Kroeze, S. J. Hufeisen, B. A. Popadak et al., “H1-histamine receptor affinity predicts short-term weight gain for typical and atypical antipsychotic drugs,” Neuropsychopharmacology, vol. 28, no. 3, pp. 519–526, 2003.
[33]
R. N. Waterhouse, “Determination of lipophilicity and its use as a predictor of blood-brain barrier penetration of molecular imaging agents,” Molecular Imaging & Biology, vol. 5, no. 6, pp. 376–389, 2003.
[34]
V. Shalgunov, J. P. van Wieringen, H. M. Janssen, et al., “Synthesis and evaluation in rats of the dopamine D2/3 receptor agonist 18F-AMC20 as potential radioligand for PET,” Journal of Nuclear Medicine, 2014.
