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    • A second advance came with the discovery

    2019-07-10

    A second advance came with the discovery that conformationally-flexible benzamide analogs having an N-phenylpiperazine moiety possessed good affinity and modest selectivity for D3 versus D2 receptors [3,[14], [15], [16]]. This observation spawned a significant effort by medicinal chemists to develop antagonists having both a high D3 affinity and excellent selectivity versus D2 receptors [2,17]. The high selectivity of the resultant compounds was attributed to the binding of the benzamide fragment to a “secondary binding site” which was initially identified through in silico modeling studies of the D3 and D2 receptors and later confirmed from the X ray crystal structure of the human D3 receptor with eticlopride, a high affinity D2/D3 antagonist, bound to the orthosteric binding site [[18], [19], [20]]. The crystal structure has led to a further identification of D3 ligands through computational screening of large compound libraries [21]. The availability of D3-selective ligands has enabled study of the distinct roles of D2 and D3 receptors both in vivo and in vitro. For example, behavioral pharmacology studies have indicated that the D3 receptor plays an important role in mediating the reinforcing effects of psychostimulants such as cocaine [17,22]. Several in vivo studies of the efficacy of D3 receptor-targeting treatments for schizophrenia and addiction are now underway [3,23]. Furthermore, in vitro autoradiography studies in control human CORM-3 sections and diffuse Lewy body disease (DLBD) including both dementia with Lewy bodies and Parkinson disease dementia revealed an increase in D3 receptor density in striatal regions but no change in D2 receptors [24], and the D3 receptor is thought to play a key role in mediating l-DOPA-induced dyskinesia [[24], [25], [26]]. PET is a functional imaging modality that is often used to image receptor availability and function, with D2-like receptors being the most comprehensively studied receptors in the central nervous system. However, the ability to investigate the unique roles of D2-like receptors in dopaminergic pathways has been limited by current radiotracers binding to both D2 and D3 receptors. Reports of PET imaging of a D3-selective radiotracer in nonhuman primates [27] coupled with identification of five distinct scaffolds for high affinity D3-selective ligands [[28], [29], [30], [31], [32]] motivate this review of the selectivity of probes for PET imaging of dopamine D3 receptors and proposed method for assessing the in vivo selectivity of D3-targeting radioligands.
    Current PET imaging of dopamine D3 receptors in humans There are four radiotracers that have been largely used in human PET imaging studies that primarily target only D2-like receptors: 1) [11C]raclopride [33]; 2) [11C]FLB 457 [34]; 3) [18F]fallypride [35]; and 4) [11C]-(+)-PHNO [36]. [11C]Raclopride, a non-selective dopamine D2/D3 antagonist initially reported by the group at the Karolinska Institute in the mid-1980s, is the most established [37,38] of the four. [11C]FLB 457, a non-selective dopamine D2/D3 antagonist, has a higher signal-to-background uptake in extrastriatal regions than [11C]raclopride [34]. However, in 2011 a D2/D3 blocking study with aripiprazole reported [11C]FLB 457 has significant specific binding in the cerebellum reference region and advised caution when interpreting results calculated using popular, blood-sample-free, reference tissue methods [39]. [18F]Fallypride, a non-selective dopamine D2/D3 antagonist developed about a decade later than [11C]raclopride, has a low level of nonspecific binding and has the advantage of having a longer 110 min half-life of fluorine-18. Consequently, [18F]fallypride is the preferred radiotracer for imaging extrastriatal D2-like receptors [35,40,41]. [11C]Raclopride has an affinity for D2 and D3 receptors in the low nM range whereas [18F]fallypride has a sub-nM affinity for both receptors [42] as shown in Fig. 1. Therefore, PET studies with [11C]raclopride and [18F]fallypride provide a measurement of the D2/D3 binding potential [[43], [44], [45], [46]]. [11C]Raclopride PET brain imaging proved instrumental in understanding D2/D3 receptor changes that occur in cocaine dependency, nicotine use, and Parkinson’s disease [47,48]. Furthermore, the availability of these tracers permitted dynamic visualization and measurement of dopamine release in response to a given challenge such as smoking or methylphenidate [49,50]. More recently, such challenges have been visualized as dynamic movies [51]. Both [11C]raclopride and [18F]fallypride have been used to determine receptor occupancy of antipsychotics used in the treatment of schizophrenia [52,53].