New N-aryl-N′-(3-(substituted)phenyl)-N′-methylguanidines as leads to potential PET radioligands for imaging the open NMDA receptor

Abstract

An expansive set of N-aryl-N’-(3-(substituted)phenyl)-N’-methylguanidines was prepared in a search for new leads to prospective PET ligands for imaging of the open channel of the N-methyl-D-aspartate (NMDA) receptor in vivo. The N-aryl rings and their substituents were varied, whereas the N-methyl group was maintained as a site for potential labeling with the positron-emitter, carbon-11 (t1/2 = 20.4 min). At micromolar concentration, over half of the prepared compounds strongly inhibited the binding of [3H]TCP to its binding site in the open NMDA receptor in vitro. Four ligands displayed affinities that are similar or superior to those of the promising SPECT radioligand ([123I]CNS1261). The 3’-dimethylamino (19; Ki 36.7 nM), 3’-trifluoromethyl (20; Ki 18.3 nM) and 3’-methylthio (2; Ki 39.8 nM) derivatives of N-1-naphthyl-N’-(phenyl)-N’-methylguanidine were identified as especially attractive leads for PET radioligand development.

N′-3-(Trifluoromethyl)phenyl Derivatives of N-Aryl-N′-methylguanidines as Prospective PET Radioligands for the Open Channel of the N-Methyl-d-aspartate (NMDA) Receptor: Synthesis and Structure–Affinity Relationships

“…We had found that replacement of the N ′-3-iodo substituent of 3 with an N ′-3-trifluoromethyl substituent gave nearly a 2-fold increase in binding affinity at the PCP binding site. 20 Retention of this 3-trifluoromethyl substituent in further analogues was seen as attractive for two main reasons. First, an aryl trifluoromethyl group is generally considered metabolically stable and would also evade the deiodination encountered in vivo with [ 123 I] 3 .…”

“…All current radioligands appear to suffer from at best low specific binding, whereas many others suffer from low brain uptake, high nonspecific binding, or confounding metabolism. 8,9 Among these radioligands, members of the N , N ′-diarylguanidine class have shown the highest affinity, 12–20 and members of the N -(1-naphthyl)- N ′-aryl- N ′-methylguanidine subclass the most potential for molecular imaging. 12,13,19,20 This is illustrated with the radioligand [ 123 I] 3 .…”

“…8,9 Among these radioligands, members of the N , N ′-diarylguanidine class have shown the highest affinity, 12–20 and members of the N -(1-naphthyl)- N ′-aryl- N ′-methylguanidine subclass the most potential for molecular imaging. 12,13,19,20 This is illustrated with the radioligand [ 123 I] 3 . SPECT studies with [ 123 I] 3 21–23 have displayed perhaps the best evidence of an NMDA-specific signal in vivo, albeit a small signal.…”

“…20 Higher affinity PET radioligands with moderate lipophilicity are sought to improve the prospects of attaining a higher PCP-site specific signal in vivo. In this study, we sought to discover higher affinity ligands that would be amenable to labeling with carbon-11 ( t 1/2 = 20.4 min) or fluorine-18 ( t 1/2 = 109.8 min) for PET imaging, based on N ′-3-trifluoromethyl members of the N -aryl- N ′-methylguanidine class of ligands, and especially a subclass with naphthalen-1-yl as the N -aryl group.…”

Selected PET Radioligands for Ion Channel Linked Neuroreceptor Imaging: Focus on GABA, NMDA and nACh Receptors

“…89 The autoradiography studies showed specific binding in rat brain cryosections and blocking studies demonstrated an up to 32% reduction of tracer binding, which represents a promising radiotracer for imaging NR2B subunit ( Figure 3b , compound e). It is worthy of mention that other approaches, including NMDA SPECT agents, 90 radiolabeled drug candidate ASP0777 91 , a NR2A selective radioligand [ 18 F]FP-PEAQX 92 and an array of candidate compounds based on CNS 1261, 93 are also disclosed in the literature in the pursue of NMDA imaging ligand.…”