Diffusion-weighted magnetic resonance imaging (DWI) is capable of noninvasively imaging acute cerebral ischemia. The authors demonstrate the utility of this technique by evaluating SNX-111, a novel N-type calcium channel blocker with potential neuroprotective properties, in a rodent model of transient focal ischemia. Twenty-four Sprague-Dawley rats weighing between 310-350 g underwent occlusion of the middle cerebral artery (MCAO) for 105 min followed by 22.5 h of reperfusion. Thirty minutes following MCAO, animals were randomized to receive SNX-111 5 mg/kg intravenously over 1 h vs. placebo. DWI and T2-weighted MRIs (T2W) were performed at 0.5, 1.5 and 24 h after the onset of ischemia. Area fractions of increased signal intensity on the DWI and T2W images were measured. DWI area fractions at 1.5 and 24 h were also normalized to the initial, pre-treatment scans. Apparent diffusion coefficients (ADC) were calculated from fitted maps. Tri-phenyl tetrazolium chloride (TTC) staining was performed on brains at 24 h and infarct area fractions were measured. SNX-111 treated animals showed significantly improved 1.5-h DWI scan ratios compared to controls (ratios of 1.06 +/- 0.25 vs. 2.98 +/- 0.78 SNX vs. controls respectively, P < 0.05). A trend toward improved DWI ratios was seen by 24 h in the SNX-111 group (2.5 +/- 0.75 vs. 4.12 +/- 1.6, N.S.) DWI, T2W and TTC area fractions at 24 h also showed trends favoring a neuroprotective effect of SNX-111. Bright areas on DWI corresponded to ADC decreases of about 30% compared to the non-ischemic hemisphere. These decreases were the same in both treatment groups and at each time point. DWI, T2W and TTC area fractions at 24 h were strongly correlated (r = 0.98, DWI and TTC; r = 0.99, T2W and TTC; r = 0.97, T2W and DWI, P < 0.0001). The authors conclude that in this ischemic model, SNX-111 provides early neuroprotection and that serial DWI is a useful way of demonstrating this.