N-{2-[4-(4-[125I]Iodobenzyl)-piperidin-1-ylmethyl]benzoimidazol-5-yl}-methanesulfonamide

Excerpt

The N-methyl-d-aspartate (NMDA) receptor (NMDAR) belongs to a sub-group of the glutamate receptor family and has a heteromeric structure that is made up of three subunits (NR1, NR2, and NR3) as dimeric combinations (NR1/NR2 or NR1/NR3). There are four subtypes of NR2 (NR2A–NR2D), and NR3 has two subtypes, NR3A and NR3B. The NMDAR can bind several different types of ligands and has important functions in the process of learning and in the performance of memory tasks in a variety of animal species (invertebrate and vertebrate) (1, 2). These receptors are involved in the development of neurological conditions such as Parkinson’s disease, Alzheimer’s disease, bipolar disorder, etc (2, 3). The structure, distribution, and function of the NMDAR in the rodent brain has been reviewed elsewhere (1, 4). The NR1 subunit of the NMDAR is known to be distributed in all parts of the brain; of the different NR2 subtypes, NR2A is found throughout the brain, whereas NR2B, NR2C, and NR2D are present mainly in the forebrain (including the cerebral cortex, hippocampus, and the olfactory lobes), cerebellum, and the lower brain stem, respectively. High levels of the NR3A subtype are detected in many brain regions of only prenatal and newborn mice, whereas NR3B levels are low during these developmental stages. However, the NR3 subtype is expressed predominantly in the adult brain (4).

Among the different NR2 and NR3 subunits, primarily the NR2B subunit is believed to modulate the various physiological and pharmacological activities of the NMDAR as mentioned above. Attempts to study the distribution of the NMDAR that contains the NR2B subunit in the brain through the use of positron emission tomography with radiolabeled compounds have been unsuccessful because the tracers lack binding specificity for the receptor (3). However, among these tracers, inspite of a high non-specific uptake of 6-{3-[4-(4-fluorobenzyl)piperidino]propionyl}-3H-benzoxazol-2-[¹¹C]-one ([¹¹C]EMD-95885; a benzimidazole derivative) in the rodent brain the amount of radioactivity in the organ was reduced by pretreatment of the animals with ifenprodil, a selective antagonist of the NR2B subunit, suggesting that [¹¹C]EMD-95885 could be a suitable platform for the development of new imaging probes to study the location and distribution of the NMDAR that contains the NR2B subunit in the rodent brain (3). Results from in vitro assays demonstrated that novel compounds with a structure resembling EMD-95885 maintained their affinity for the NR2B subunit (5). On the basis of this information, Fuchigami et al. synthesized a series of [¹²⁵I]-labeled benzimidazole derivatives and investigated their in vitro receptor binding and in vivo brain uptake characteristics in normal mice (3). Among these radioiodinated compounds, only two, 2-{[4-(4-[¹²⁵I]iodobenzyl)piperidin-1-yl]methyl}benzimidazol-5-ol ([¹²⁵I]8) and N-{2-[4-(4-[¹²⁵I]iodobenzyl)-piperidin-1-ylmethyl]benzoimidazol-5-yl}-methanesulfonamide ([¹²⁵I]9), were shown to have a high affinity for the NR2B subunit under in vitro conditions. This chapter discusses the in vitro and in vivo results obtained with [¹²⁵I]9; the characteristics of [¹²⁵I]8 are described in a separate chapter of MICAD (www.micad.nih.gov) (6).