Development Of New Approaches To Neuroimaging with PET a

National Institute On Drug Abuse

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Abstract

The ability to image and quantify nicotinic receptors in human brain may be crucial to better understanding the neurobiology of smoking addiction. The interaction of nicotine with high affinity nicotinic acetylcholine receptors in the brain (predominantly the alpha4beta2 subtype) is thought to mediate the rewarding and addictive properties of tobacco smoke. The literature shows that assays of high affinity nicotinic acetylcholine receptors in human postmortem brain tissue revealed that smokers have higher densities than non-smokers or exsmokers in several brain regions. The goal of the current study was to determine if these differences could be shown in vivo with positron emission tomography (PET) and to determine the neuroanatomical extent of the difference. In this study, we used dynamic PET imaging with 2[F-18]F-A-85380 to measure total volumes of distribution (VD) in non-smokers (n=10) and heavy smokers (>14 cigarettes/day; abstinent for >36 h, n=7). Dynamic PET scans were obtained in a Siemens EXACT HR+ scanner over 8 h commencing immediately after a bolus injection of 2[F-18]F-A-85380. Dynamic PET images were motion and decay corrected and anatomical sampling was performed on modeled PET images that were coregistered to MRI scans acquired from each volunteer. Values for total volumes of distribution (VDtot) were obtained. Logan plots, as well as 1- and 2-tissue compartment models using a metabolite-corrected arterial input function for 2[F-18]F-A-85380 all yielded similar results. Regions sampled included thalamus (TH), midbrain (MB), pons (P), cerebellum (CB), frontal cortex (FC), putamen (PUT) and corpus callosum (CC). For smokers and nonsmokers, VDtot was highest in TH > MB > P > CB > FC > PUT and lowest in CC. VDtot was significantly higher (p<0.01) in smokers than in nonsmokers in CB, FC, MB, P and PUT. Using VDtot for the corpus callosum in nonsmokers as an estimate of nondisplaceable VD, we found 30% to more than 200% higher values for the specific binding compartment (VDsb) in smokers compared to non-smokers in these brain regions. PET imaging of nicotinic receptors with 2-[F-18]F-A-85380 shows that the greater density of these receptors in smokers compared to controls can be observed in vivo and suggests that PET studies with 2[F-18]F-A-85380 can be used to study the role of nicotine-induced upregulation of nicotinic receptors in smoking behaviors and in smoking cessation.[unreadable] Various methods for quantifying cerebral receptors using PET have been developed. Most of these methods require an arterial blood input function and therefore are invasive and inconvenient in humans or in small animals. The reference tissue approach requires a satisfactory reference region in the brain, which is often unavailable. Due to these limitations, we explored the potential of using an extra-cerebral area for quantification of central receptors. If the ratio between the volume of distribution (VD) of non-displaceable compartment in the region of interest (VDnd) and the VD of the reference region inside or even outside of the brain is constant and known, then theoretically it is possible using the accumulation radioactivity in reference region and region of interest over time to calculate the value of apparent binding potential (BP*). To validate this approach, we performed quantitative PET studies of alpha4beta2* nicotinic acetylcholine receptors with 2[F-18]fluoro-A-85380 in squirrel monkeys. Total VD and BP* values in several brain areas were calculated using an arterial blood input function or data from a reference region inside (cerebellum, Cb) and outside (muscle) of the brain using the simplified reference tissue model. When muscle was used as the reference region, BP* values were corrected for the difference between VD in muscle and VDnd. VD total and BP* values were highest in the thalamus and lowest in cerebellum and muscle, consistent with the distribution pattern of alpha4beta2* nicotinic acetylcholine receptors in primates. Limited (9?4% for Cb) or no displacement (for muscle) of radioligand by nicotine was observed, indicating the limited specific binding of 2[F-18]F-A-85380 in these regions. These results suggest that quantifying central receptors is feasible using an extra-cerebral reference region, providing a novel approach for quantification of brain receptors when no suitable reference region inside the brain exists. [unreadable] Mice studies showed that the administration of the non-selective inhibitor of cytochrome P450, cimetidine, substantially slowed the rapid in vivo metabolism of 5[I-123]I-A-85380, suggesting that the use of this or similar compounds could reduce the dose of radioactivity needed to successfully image nicotinic acetylcholine receptors in human volunteers. In collaboration with researchers from the University of Michigan, the loss of nicotinic acetylcholine receptors in the striatum of an animal model for Parkinson's disease, unilaterally MPTP-lesioned nonhuman primates, with 2[F-18]F-A-85380 and PET was demonstrated. [unreadable] Imaging of the central CB1 cannabinoid receptors by PET will improve our understanding of the roles of these receptors in the brain. Existing PET radiotracers for imaging CB1 are very lipophilic compounds with high non-specific to specific binding ratios and as a result are not adequate for quantitative studies. A 14-member series of analogs of 1-[(N-methyl-piperidin-2-yl)methyl]-3-naphthoylindole, a CB1 agonist with high binding affinity, with reduced lipophilicities has been synthesized. The lead compound shows a Ki of 0.9 nM, which represents one of the highest affinities observed for CB1 receptor ligands; further, it has a cLogD value, which should reduce non specific accumulation of the radioligand.