[11C]Cyclopropyl-FLB 457: A PET radioligand for low densities of dopamine D2 receptors (original) (raw)
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Journal of Medicinal Chemistry, 1988
From salicyclic acid, the two enantiomers of N-[ (l-ethyl-2-pyrrolidinyl)methyl]-5-iodo-2-methoxybenzamide (6b) were prepared in a five-step synthesis. With use of Heindel's triazene method for introduction of the radionuclide, the iodine-125-labeled substituted benzamide was obtained with a calculated specific activity of 136 Ci/mmol and 14 % radiochemical yield. For the preparation of the iodine-125-labeled benzamide with higher specific activity, this method was unsuccessful and utilization of the corresponding tri-n-butyltin derivative was required. Treatment of the latter in dilute hydrochloric acid with sodium iodide125 and chloramine-T gave [1251](S)-6b in 56% radiochemical yield and at least 97% radiochemical purity. The displacement of ['%I](S)-Gb and [3H](S)-sulpiride from their respective binding sites in striatal rat brain homogenate5 using various neuroleptic agents showed that (S)-6b has the same binding profile but more potent binding for dopamine D-2 receptors than has sulpiride. These experiments also indicate that the S enantiomer of 6b is a specific ligand (KD = 1.2 IN) for the D-2 receptor. Further, the octanol-water partition coefficient of (S)-6b as determined by reverse-phase high-performance liquid chromatography was found to be 40 times greater than that for sulpiride. Thus (S)-6b has a lipophilicity that will allow a relatively higher uptake into the brain compared to sulpiride. In vivo experiments with rats show that [1261](S)-6b penetrates readily into the brain and is preferentially localized in the striatum as compared to the cerebellum, the ratio of uptake being 7.2 to 1,60 min after injection. These observations of good brain penetration and high affinity and selectivity for D-2 recepton indicate that the corresponding iodine-123-labeled benzamide may be a useful ligand for the noninvasive visualization study of dopamine D-2 receptor sites in vivo by single photon emission computed tomography. amine D-2 r e~e p t o r ,~'~ the receptor having been implicated in t h e antipsychotic action of neuroleptic agents. 4-[1251]Iodospiperone (2c) in comparison with tritiated spiperone, however, was shown not t o be a useful ligand for
Synapse, 2010
4-(Dimethylamino)-N-(4-(4-(2-methoxyphenyl)piperazin-1-yl)butyl)benzamide (WC-10), a Nphenyl piperazine analog, displays high affinity and moderate selectivity for dopamine D 3 receptors versus dopamine D 2 receptors Bioorg. Med. Chem. 13;[77][78][79][80][81][82][83][84][85][86][87]. In this study, WC-10 was radiolabeled with tritium (specific activity = 80 Ci/mmol) and quantitative autoradiography studies were conducted using rhesus monkey and Sprague-Dawley rat brain sections. K d values for the binding of [ 3 H]WC-10 to D 3 receptors obtained from quantitative autoradiography with rhesus monkey and rat brain sections are in agreement with K d values obtained from cloned human and rat receptors ). The D 2 selective antagonist [ 3 H]raclopride binds with 11-fold higher affinity to human HEK D 2L (K d = 1.6 nM) than HEK D 3 (K d = 18 nM) receptors; and [ 3 H]raclopride binds to rat Sf9 rD 2L receptors with a K d of 6.79 nM, a value that is 4-fold lower than binding to human HEK D 2L receptors and 2.5-fold higher than binding to rat Sf9 rD 3 receptors. In vitro quantitative autoradiography studies with [ 3 H]WC-10 and [ 3 H]raclopride were conducted on adult rat and rhesus monkey brain sections. A mathematical model for calculating the absolute densities of dopamine D 2 and D 3 receptors based on the in vitro receptor binding data of [ 3 H]WC-10 and [ 3 H]raclopride was developed.
NeuroImage, 2013
Positron emission tomography (PET) is an imaging technique able to provide detailed spatial-temporal functional data of the cerebral neurotransmission system. The dopaminergic pathway has been largely characterized with PET imaging due to the existence of large number of radiotracers available to bind to the different targets of this system. Thus, the selection of the radiotracer depends on the particular aspect of the dopaminergic system to be studied. In this chapter, a methodological PET study of the D 2 /D 3 receptor bioavailability with [ 11 C]raclopride is described. Likewise, the preparation steps for the synthesis of [ 11 C]raclopride as well as the protocols of PET/CT acquisition, reconstruction, and quantifi cation of the data are presented.
Nuclear Medicine and Biology, 2014
Introduction: Dopamine D3 receptors are implicated in various neuropsychiatric diseases, drug abuse and alcoholism, but specific agents for D3 molecular imaging are lacking. We evaluated two in vitro selective fluorine-18-labeled radioligand candidates ([ 18 F]5 and [ 18 F]6) for positron emission tomography (PET) imaging of D3 receptor availability in the brain. Methods: Biodistribution was evaluated in Sprague-Dawley rats using ex vivo autoradiography and smallanimal PET. Protein binding studies were conducted in human plasma and cerebrospinal fluid. Results: [ 18 F]5 showed rapid blood-brain barrier penetration and fast washout after intravenous injection, whereas the rat brain penetration of [ 18 F]6 was lower. The total distribution volume (V T) of [ 18 F]5 was 20-26 mL g −1 throughout brain. Co-injection with the D3 antagonist BP897 resulted in globally increased cerebral washout of [ 18 F]5 and [ 18 F]6, but SUV analysis and parametric mapping of binding potential (BP ND) relative to the cerebellum did not reveal specific binding of either ligand in D3-rich brain regions, i.e. the ventral striatum. However, there was substantial displaceable binding of [ 18 F]5, and to a lesser extent [ 18 F]6, in the pituitary. Conclusion: These radioligands reveal dopamine D3 receptors in the pituitary, but are not suitable for PET imaging of in brain, possibly due to low specific signal relative to the globally high V T .