A new quantitation method for mass spectrometry imaging (MSI) with matrix-assisted laser desorption/ionization (MALDI) has been developed. In this method, drug concentrations were determined by tissue homogenization of five 10 µm tissue sections adjacent to those analyzed by MSI. Drug levels in tissue extracts were measured by liquid chromatography coupled to tandem mass spectrometry (LC/MS/MS). The integrated MSI response was correlated to the LC/MS/MS drug concentrations to determine the amount of drug detected per MSI ion count. The study reported here evaluates olanzapine in liver tissue. Tissue samples containing a range of concentrations were created from liver harvested from rats administered a single dose of olanzapine at 0, 1, 4, 8, 16, 30, or 100 mg/kg. The liver samples were then analyzed by MALDI-MSI and LC/MS/MS. The MALDI-MSI and LC/MS/MS correlation was determined for tissue concentrations of ~300 to 60,000 ng/g and yielded a linear relationship over two orders of magnitude (R(2) = 0.9792). From this correlation, a conversion factor of 6.3 ± 0.23 fg/ion count was used to quantitate MSI responses at the pixel level (100 µm). The details of the method, its importance in pharmaceutical analysis, and the considerations necessary when implementing it are presented.

ABT-089 [2-methyl-3-(2-(S)-pyrrolidinylmethoxy)pyridine dihydrochloride salt] is a selective neuronal nicotinic receptor (NNR) modulator with cognitive enhancing properties in animal models of cognitive functioning. Amongst NNR subtypes, ABT-089 shows selectivity for the cytisine binding site on the á 4 â 2 receptor subtype as compared to the á-bungarotoxin (á-BgT) binding sites on the á 7 and á 1 â 1 äã receptor subtypes. In functional in vitro electrophysiological and cation flux assays, ABT-089 displays differential activity including agonism, partial agonism and antagonism depending upon the NNR subtype and assay. ABT-089 is as potent and efficacious as (-)-nicotine at evoking acetylcholine (ACh) release from hippocampal synaptosomes. Furthermore, ABT-089 is neuroprotective against excitotoxic glutamate insults, with even greater potency seen after chronic treatment. Similarly, ABT-089 is effective in models of cognitive functioning, including enhancement of baseline functioning as well as improvement of impaired cognitive functioning seen following septal lesioning and natural aging. In neuroprotective assays the compound is most potent by chronic administration. In stark contrast to the positive effects in the cognitive models, ABT-089 shows little propensity to induce adverse 167 CNS Drug Reviews Vol. 10, No. 2, pp. 167-182 © 2004 Neva Press, Branford, Connecticut Address correspondence and reprint requests to Lynne Rueter, Abbott Laboratories, Neuroscience Research, R4N5, AP9A, 100 Abbott Park Rd., Abbott Park, IL 60064-6115, USA. Fax: +1 (847) 938-0072; E-mail: lynne.e.rueter@abbott.com effects such as ataxia, hypothermia, seizures, cardiovascular or gastrointestinal side effects. Together these data suggest that ABT-089 is a NNR modulator with the potential for treating cognitive disorders with markedly limited adverse cardiovascular and gastrointestinal side effects.

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Background and purpose: Activation of cannabinoid CB 1 and/or CB 2 receptors mediates analgesic effects across a broad spectrum of preclinical pain models. Selective activation of CB 2 receptors may produce analgesia without the undesirable psychotropic side effects associated with modulation of CB 1 receptors. To address selectivity in vivo, we describe non-invasive, non-ionizing, functional data that distinguish CB 1 from CB 2 receptor neural activity using pharmacological MRI (phMRI) in awake rats. Experimental approach: Using a high field (7 T) MRI scanner, we examined and quantified the effects of non-selective CB 1 / CB 2 (A-834735) and selective CB 2 (AM1241) agonists on neural activity in awake rats. Pharmacological specificity was determined using selective CB 1 (rimonabant) or CB 2 (AM630) antagonists. Behavioural studies, plasma and brain exposures were used as benchmarks for activity in vivo. Key results: The non-selective CB 1 /CB 2 agonist produced a dose-related, region-specific activation of brain structures that agrees well with published autoradiographic CB 1 receptor density binding maps. Pretreatment with a CB 1 antagonist but not with a CB 2 antagonist, abolished these activation patterns, suggesting an effect mediated by CB 1 receptors alone. In contrast, no significant changes in brain activity were found with relevant doses of the CB 2 selective agonist. Conclusion and implications: These results provide the first clear evidence for quantifying in vivo functional selectivity between CB 1 and CB 2