Synthesis and evaluation in rats of homologous series of [(18)F]-labeled dopamine D 2/3 receptor agonists based on the 2-aminomethylchroman scaffold as potential PET tracers (original) (raw)
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Arkivoc, 2006
Currently, the lack of a selective dopamine D 3 PET (positron emission tomography) radioligand for in vivo brain occupancy studies is problematic. Several requirements are necessary for a potential PET radioligand for visualization of a receptor into the brain: i) high affinity and selectivity for the target receptor; ii) suitable lipophilicity for both blood-brain barrier permeation and low nonspecific binding to proteins and lipids; iii) structural features that allow labelling with a positron emission isotope. In this study the synthesis and binding affinities for dopamine D 3 and D 2 receptors of several N-[4-(4-arylpiperazin-1-yl)butyl]arylcarboxamides are reported. These compounds were designed by the structural modification of the formerly reported D 3 receptor ligand N-[4-[4-(2,3-dichlorophenyl)piperazin-1-yl]butyl]-7-methoxy-2benzofurancarboxamide (1), with the aim to obtain a suitable lipophilicity and the structural features for labelling. In particular, both the 2,3-dichlorophenyl group and the 7-methoxy-2benzofurancarboxamide moiety were replaced by less lipophilic fragments. Among the studied compounds, derivatives N-[4-[4-(5-methoxy-2-benzisoxazolyl)piperazin-1-yl]butyl]-4-(4morpholinyl)benzamide (20), N-[4-[4-(5-methoxy-2-benzisoxazolyl)piperazin-1-yl]butyl]-4-(1Himidazol-1-yl)benzamide (21), and N-[4-[4-(5-methoxy-2-benzisoxazolyl)piperazin-1-yl]butyl]-5-(2-furanyl)-1H-pyrazole-3-carboxamide (22) displayed good D 3 receptor affinities (K i values 38, 22.6, and 21.3 nM, respectively) and were found to be inactive at D 2 receptor. Moreover, on the basis of their experimental log P values and their ability to cross the Caco-2 monolayer, compounds 20-22 are likely to permeate the blood-brain barrier, differently from compound 1.
Bioorganic & Medicinal Chemistry, 2005
D 3 receptor radioligands (E)-4,3,2-[ 11 C]methoxy-N-4-(4-(2-methoxyphenyl)piperazin-1-yl)butyl-cinnamoylamides (4-[ 11 C]MMC, [ 11 C]1a; 3-[ 11 C]MMC, [ 11 C]1b; and 2-[ 11 C]MMC, [ 11 C]1c) were synthesized for evaluation as novel potential positron emission tomography (PET) imaging agents for brain D 3 receptors. The new tracers 4,3,2-[ 11 C]MMCs were prepared by O-[ 11 C]methylation of corresponding precursors (E)-4,3,2-hydroxy-N-4-(4-(2-methoxyphenyl)piperazin-1-yl)butyl-cinnamoylamides (4,3,2-HMCs) using [ 11 C]methyl triflate and isolated by the solid-phase extraction (SPE) purification procedure with 40-65% radiochemical yields, decay corrected to end of bombardment (EOB), and a synthesis time of 15-20 min. The PET dynamic studies of the tracers [ 11 C]1a-c in rats were performed using an animal PET scanner, IndyPET-II, developed in our laboratory. The results show that the brain uptake sequence was 4-[ 11 C]MMC > 3-[ 11 C]MMC > 2-[ 11 C]MMC, which is consistent with their in vitro biological properties. The initial PET blocking studies of the tracers 4,3,2-[ 11 C]MMCs with corresponding pretreatment drugs (E)-4,3,2-methoxy-N-4-(4-(2-methoxyphenyl)piperazin-1-yl)butyl-cinnamoylamides (4,3,2-MMCs, 1a-c) had no effect on 4,3,2-[ 11 C]MMCs-PET rat brain imaging. These results suggest that the localization of 4,3,2-[ 11 C]MMCs in rat brain is mediated by nonspecific processes, and the visualization of 4,3,2-[ 11 C]MMCs-PET in rat brain is related to nonspecific binding.
Synthesis and Pharmacological Evaluation of Fluorine-Containing D3 Dopamine Receptor Ligands
Journal of Medicinal Chemistry, 2011
A series of fluorine containing N-(2-methoxyphenyl)piperazine and N-(2-fluoroethoxy)piperazine analogues were synthesized and their affinities for human dopamine D 2 , D 3 and D 4 receptors were determined. Radioligand binding studies identified five compounds, 18a, 20a, 20c, 20e and 21e, which bind with high affinity at D 3 (K i = 0.17 to 5 nM) and moderate to high selectivity for D 3 vs. D 2 receptors (ranging from ∼25 to 163-fold). These compounds were also evaluated for intrinsic activity at D 2 and D 3 receptors using a forskolin-dependent adenylyl cyclase assay. This panel of compounds exhibits varying receptor subtype binding selectivity and intrinsic activity at D 2 vs. D 3 receptors. These compounds may be useful for behavioral pharmacology studies on the role of D 2like dopamine receptors in neuropsychiatric and neurological disorders. Furthermore, compound 20e, which has the highest binding affinity and selectivity for the D 3 receptor (K i = 0.17 nM for D 3 , 163-fold selectivity for D 3 vs. D 2 receptors) represents a candidate fluorine-18 radiotracer for in vivo PET imaging studies on the regulation of D 3 receptor expression.
Synapse, 1996
The purpose of the present set of studies was to characterize, in vitro and in vivo, two benzamide analogues, 2,3-dimethoxy-N-[l-(4-fluorobenzyl)piperidin-4yllbenzamide (MBP) and 4'-fluoroclebopride (FCP), for studying dopamine D2 receptors with Positron Emission Tomography (PET). In vitro binding studies were conducted to determine the affinities of MBP and FCP to the three subtypes of dopamine D2 receptors: D2(iong,, D,?, and D, receptors. MBP was found to have a high affinity (K, = 1-8 nM) for all three subtypes of the D2 receptor, whereas FCP had nanomolar affinity (K, -5.5 nM)
European Journal of Pharmacology, 1993
High affinity and selective fluorinated derivatives of 7-chloro-8-hydroxy-3-methyl-l-(3'-aminophenyl)-2,3,4,5-tetrahydro-lH-3benzazepine (SCH 38548) for dopamine D 1 receptors have been prepared. The derivatives exhibit subnanomolar to nanomolar affinities for dopamine D 1 receptors and micromolar to millimolar affinities for dopamine D 2 and 5-HT 2 receptors. Biodistribution of N-(3-[lSF]fluoropropyl)SCH 38548 in rats showed specific uptake and retention (0.64% injected dose/g at 30 min) of the radiotracer in the striata with striata to cerebellum ratios reaching 12 at 2 h post-injection. Preliminary positron emission tomography scans in rhesus monkeys indicate selective uptake of the radiotracer in the striata. N-(3-[~F]Fluoropropyl)SCH 38548; Dopamine D 1 receptors; PET (positron emission tomography)
Journal of Medicinal Chemistry, 2005
In vivo imaging of dopamine D2 receptors with agonist (as opposed to the more commonly employed antagonist) radiotracers could provide important information on the high-affinity (functional) state of the D2 receptor in illnesses such as schizophrenia, movement disorders, and addictions. We report here the radiosynthesis and evaluation of the potent D2 agonist (+)-4-propyl-3,4,4a,5,6,10b-hexahydro-2H-naphtho[1,2-b][1,4]oxazin-9-ol, (+)-3, labeled with carbon-11, as a potential radiotracer for imaging the high-affinity state of dopamine D2 receptors with positron emission tomography (PET). [ 11 C]-(+)-3 was reliably synthesized in the quantities and at the specific activities and radiochemical purities required for human PET studies. Ex vivo biodistribution studies in rat brain demonstrated that [ 11 C]-(+)-3 crossed the blood-brain barrier readily and had an appropriate regional brain distribution for a radiotracer that maps dopamine D2 receptors. The binding of [ 11 C]-(+)-3 was saturable and demonstrated an excellent signal-to-noise ratio as measured by its striatum-to-cerebellum ratio of 5.6, 60 min postinjection. The binding was highly stereospecific, and blocking and displacement studies were consistent with selective and specific binding to the dopamine D2 receptors. Further, [ 11 C]-(+)-3 showed marked and appropriate sensitivity to both increases and decreases in the levels of endogenous dopamine. Brain radioactive metabolite and physicochemical measurements are in full accord with the desired properties of a neuroreceptor imaging agent for PET. All of the above, coupled with the documented full D2 agonistic properties of (+)-3, strongly indicate that [ 11 C]-(+)-3 is a leading candidate radiotracer for the imaging of the dopamine D2 high-affinity state using PET in human subjects.