Summary: A graphical method of analysis applicable to ligands that bind reversibly to receptors or enzymes re quiring the simultaneous measurement of plasma and tis sue radioactivities for multiple times after the injection of a radiolabeled tracer is presented. It is shown that there is a time tt after which a plot of nROI(t')dt'/ROI(t) versus J�Cp(t')dt' IROI(t) (where ROI and Cp are functions of time describing the variation of tissue radioactivity and plasma radioactivity, respectively) is linear with a slope that corresponds to the steady-state space of the ligand plus the plasma volume, Vp. For a two-compartment model, the slope is given by >.. + Vp, where >.. is the partition coefficient and the intercept is -l I[k2(l + Vp/>.. »). For a three-compartment model, the slope is >"(1and the intercept is -{(l + BmaxlKd)lk2

The massive health problem associated with cigarette smoking is exacerbated by the addictive properties of tobacco smoke and the limited success of current approaches to cessation of smoking. Yet little is known about the neuropharmacological actions of cigarette smoke that contribute to smoking behaviour, or why smoking is so prevalent in psychiatric disorders and is associated with a decreased risk of Parkinson's disease. Here we report that brains of living smokers show a 40% decrease in the level of monoamine oxidase B (MAO B; EC 1.4.3.4) relative to non-smokers or former smokers. MAO B is involved in the breakdown of dopamine, a neurotransmitter implicated in reinforcing and motivating behaviours as well as movement. MAO B inhibition is therefore associated with enhanced activity of dopamine, as well as with decreased production of hydrogen peroxide, a source of reactive oxygen species. We propose that reduction of MAO B activity may synergize with nicotine to produce the diverse behavioural and epidemiological effects of smoking.

This study images dopamine release in response to a neurochemically specific challenge with the psychostimulant drug methylphenidate. Changes in synaptic dopamine induced by methylphenidate were evaluated with positron emission tomography and [11C]raclopride, a D2 receptor radioligand that is sensitive to endogenous dopamine. Methylphenidate significantly decreased striatal [11C]raclopride binding. The decrease was variable and was negatively correlated with age. Mood and anxiety at baseline, were also correlated with methylphenidate-induced DA changes. This strategy provides a tool to investigate the responsiveness of the dopamine system in the normal and diseased human brain and to investigate the neurochemical correlates of behavior.

Several studies have documented a strong association between smoking and depression. Because cigarette smoke has been reported to inhibit monoamine oxidase (MAO) A in vitro and in animals and because MAO A inhibitors are effective antidepressants, we tested the hypothesis that MAO A would be reduced in the brain of cigarette smokers. We compared brain MAO A in 15 nonsmokers and 16 current smokers with [ 11 C]clorgyline and positron emission tomography (PET). Four of the nonsmokers were also treated with the antidepressant MAO inhibitor drug, tranylcypromine (10 mg͞day for 3 days) after the baseline PET scan and then rescanned to assess the sensitivity of [ 11 C]clorgyline binding to MAO inhibition. MAO A levels were quantified by using the model term k 3 which is a function of brain MAO A concentration. Smokers had significantly lower brain MAO A than nonsmokers in all brain regions examined (average reduction, 28%). The mean k 3 values for the whole brain were 0.18 ؎ 0.04 and 0.13 ؎ 0.03 cc brain (ml plasma )؊1 min ؊1 for nonsmokers and smokers, respectively; P < 0.0003). Tranylcypromine treatment reduced k 3 by an average of 58% for the different brain regions. Our results show that tobacco smoke exposure is associated with a marked reduction in brain MAO A, and this reduction is about half of that produced by a brief treatment with tranylcypromine. This suggests that MAO A inhibition needs to be considered as a potential contributing variable in the high rate of smoking in depression and in the development of more effective strategies for smoking cessation.There are approximately 1 billion cigarette smokers in the world today and about 3 million die each year from smokingassociated illnesses (1). This places a sense of urgency on understanding the neuropharmacological properties of tobacco smoke and their relationship to smoking behavior and epidemiology. For example, it is not understood why smoking is more prevalent in depression and why smoking cessation is less successful in depressed patients (2, 3). Though it is unlikely that any one factor accounts for the strong association between smoking and depression, it is possible that tobacco smoke may have antidepressant properties. One of the molecular targets proposed to link smoking and depression is monoamine oxidase (MAO) (4, 5), an enzyme which was first associated with mood over 40 years ago when it was discovered that MAO inhibitors had antidepressant properties (6, 7).MAO exists in two subtypes (MAO A and B) that are different gene products (8, 9). In the brain, MAO A oxidizes serotonin and norepinephrine and is found primarily in catecholaminergic neurons, whereas MAO B oxidizes benzylamine and phenethylamine and is localized in serotonergic neurons and in glial cells (10). Both forms oxidize dopamine (11). The antidepressant effects of the nonselective MAO inhibitors are generally attributed to the inhibition of MAO A (12).We recently reported that smokers have reduced brain MAO B relative to nonsmokers and former smokers (13).Others have fo...

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The rate constants and lumped constants (LCs) for [18F]fluorodeoxyglucose ([18F]FDG) and [11C]deoxyglucose ([11C]DG) were determined in humans for the glucose metabolic rate kinetic model used to measure local cerebral glucose consumption. The mean values (+/- SE) of the LCs for [18F]FDG and [11C]DG are 0.52 +/- 0.028 (n = 9) and 0.56 +/- 0.043 (n = 6), respectively. The mean values (+/- SE) of the rate constants k*1, k*2, k*3, and k*4 for [18F]FDG for gray matter are 0.095 +/- 0.005, 0.125 +/- 0.002, 0.069 +/- 0.002, and 0.0055 +/- 0.0003, respectively. The corresponding values for white matter are 0.065 +/- 0.005, 0.126 +/- 0.003, 0.066 +/- 0.002, and 0.0054 +/- 0.0006, respectively. Using these values and previously published values for the rate constants for [11C]DG, the average whole-brain metabolic rates for glucose in normal subjects measured with [18F]FDG and [11C]DG are 5.66 +/- 0.37 (n = 6) and 4.99 +/- 0.23 (n = 6) mg/100 g/min, respectively. These values are not significantly different (t = 1.56, p greater than 0.10) and agree well with reported values in the literature determined by means of the Kety-Schmidt technique.

The first direct measurements of cocaine binding in the brain of normal human volunteers and baboons have been made by using positron emission tomography (PET) and tracer doses of [N-11C-methyl]-(-)-cocaine ([11C]cocaine). Cocaine's binding and release from brain are rapid with the highest regional uptake of carbon-11 occurring in the corpus striatum at 4-10 minutes after intravenous injection of labeled cocaine. This was followed by a clearance to half the peak value at about 25 minutes with the overall time course paralleling the previously documented time course of the euphoria experienced after intravenous cocaine administration. Blockade of the dopamine reuptake sites with nomifensine reduced the striatal but not the cerebellar uptake of [11C]cocaine in baboons indicating that cocaine binding is associated with the dopamine reuptake site in the corpus striatum. A comparison of labeled metabolites of cocaine in human and baboon plasma showed that while cocaine is rapidly metabolized in both species, the profile of labeled metabolites is different, with baboon plasma containing significant amounts of labeled carbon dioxide, and human plasma containing no significant labeled carbon dioxide. These studies demonstrate the feasibility of using [11C]cocaine and PET to map binding sites for cocaine in human brain, to monitor its kinetics, and to characterize its binding mechanism by using appropriate pharmacological challenges.

The regional distributions of monoamine oxidase (MAO) types A and B have been identified in human brain in vivo with intravenously injected 11C-labeled suicide enzyme inactivators, clorgyline and L-deprenyl, and positron emission tomography. The rapid brain uptake and retention of radioactivity for both 11C tracers indicated irreversible trapping. The anatomical distribution of 11C paralleled the distribution of MAO A and MAO B in human brain in autopsy material. The corpus striatum, thalamus, and brainstem contained high MAO activity. The magnitudes of uptake of both [11C]clorgyline and L-[11C]deprenyl were markedly reduced in one subject treated with the antidepressant MAO inhibitor phenelzine. A comparison of the brain uptake and retention of the 11C-labeled inactive (D-) and active (L-) enantiomers of deprenyl showed rapid clearance of the inactive enantiomer and retention of the active enantiomer within MAO B-rich brain structures, in agreement with the known stereoselectivity of MAO B for L-deprenyl. Prior treatment with unlabeled L-deprenyl prevented retention of L-[11C]deprenyl. Thus, suicide enzyme inactivators labeled with positron emitters can be used to quantitate the distribution and kinetic characteristics of MAO in human brain structures.