Novel Series of Dihydropyridinone P2X7 Receptor Antagonists.

Identification of singleton P2X7 inhibitor 1 from HTS gave a pharmacophore that eventually turned into potential clinical candidates 17 and 19. During development, a number of issues were successfully addressed, such as metabolic stability, plasma stability, GSH adduct formation, and aniline mutagenicity. Thus, careful modification of the molecule, such as conversion of the 1,4-dihydropyridinone to the 1,2-dihydropyridinone system, proper substitution at C-5″, and in some cases addition of fluorine atoms to the aniline ring allowed for the identification of a novel class of potent P2X7 inhibitors suitable for evaluating the role of P2X7 in inflammatory, immune, neurologic, or musculoskeletal disorders.

Design, construction, and validation of an MRI-compatible vibrotactile stimulator intended for clinical use.

Vibrotactile stimulation has been used successfully to activate the human somatosensory pathway in functional magnetic resonance imaging (fMRI) experiments. The design and characterization of these devices are of particular interest in frequency discrimination tasks and investigations of the somatopic organization of sensory areas. However, few have investigated the utility of vibrotactile stimulation in a clinical context. We have previously demonstrated that vibrotactile stimulation can provide robust activations in areas targeted in stereotactic functional neurosurgical procedures used for tumour resection (i.e.: primary and secondary somatosensory areas) and subcortical targets for thalamic pain and movement disorders (i.e.: sensory thalamus). The main contribution of this manuscript is the presentation of the design, materials, construction, and validation of a novel vibrotactile stimulator intended for clinical use. The thalamic activations are also compared to a digital atlas in order to evaluate anatomical localization. The proposed stimulator was constructed entirely from non-ferromagnetic parts, uses compressed air to deliver stimulation using computer control, and stimulates the entirety of the hand and fingers to ensure robust somatosensory activations. In addition, this stimulator is constructed entirely from "off-the-shelf" parts and would be easily replicated due to the simplicity of design and the relatively small expense of the parts required. The device was tested by stimulating the right hand of 10 normal controls (5 females, 5 males, all right handed; age range: 25-42 years, mean: 30.9 years, standard deviation: 5.2 years) during an fMRI experiment. The results demonstrate significant single subject activations of primary and secondary somatosensory cortices and of the sensory thalamus.

Robust S1, S2, and thalamic activations in individual subjects with vibrotactile stimulation at 1.5 and 3.0 T.

Functional magnetic resonance imaging (fMRI) is often used to enhance visualization and provide target localization during the planning phase of neurosurgical procedures. Although parametric maps have been used to identify areas of eloquent cortex such as the primary (S1) and secondary (S2) somatosensory areas for tumor surgery, to date, few fMRI methods exist to localize subcortical targets for surgical interventions used to treat movement disorders. The scanning time required to obtain statistically significant functional signals must be balanced against the possibility of movement artifacts and patient discomfort. We propose a vibrotactile stimulation technique to activate the somatosensory pathway for neurosurgical planning and perform a sensitivity analysis to determine the amount of time required to achieve significant activations of S1, S2, and sensory thalamus in individual subjects. Bilateral stimulation experiments were carried out on two MRI scanners (n = 13 at 1.5 T; n = 5 at 3.0 T). The analysis demonstrates that statistically significant functional activations can be achieved in clinically acceptable times: 16 min at 1.5 T (26/26 experiments) and 6 min at 3.0 T (10/10) for S1 activations; 24 min at 1.5 T (22/26) and 18 min at 3.0 T for S2 activations (9/10); and 32 min at 1.5 T (15/26) and 18 min at 3.0 T (10/10) for activation of thalamic nuclei. These results demonstrate that S1 and S2 activations are robust at 1.5 and 3.0 T, and that robust thalamic activations in individual subjects are possible at 3.0 T. These techniques demonstrate that this technique can be used for preoperative planning for surgical candidates.