The Assay of Enzyme Activity by Positron Emission Tomography

  • Paul Cumming
  • Neil Vasdev
Part of the Neuromethods book series (NM, volume 71)


In a relatively small number of instances, the activity in brain of specific enzymes can be measured with positron emission tomography (PET) using radioactive enzyme substrates in conjunction with compartmental modeling. Thus, the trapping of [11C]-labeled amino acids in brain protein was an early application of PET, which has found particular use in the detection of brain tumors. The most successful PET agent remains the glucose analog [18F]-fluoro-deoxyglucose (FDG), which is trapped in brain as FDG-phosphate, at a rate determined by the local activity of the hexokinase enzyme. The integrity of nigrostriatal dopamine innervations can be assessed with the DOPA decarboxylase tracer [18F]-fluoro-l-DOPA (FDOPA), whereas the rate of serotonin synthesis has been measured in PET studies with α-[14C]-methyl-l-tryptophan. Monoamine oxidase, uniquely, can be assessed in PET studies with suicide substrates such as l-[11C]-deprenyl, where the rate of trapping in living tissue is a function of the local catalytic activity of MAO-B. However, the abundance of MAO-A is most conveniently assessed with [11C]-harmine and other competitor ligands, which bind reversibly to the enzyme. [11C]-PMP and a number of other substrates for acetylcholine esterase have been developed, based on the production in situ of a nondiffusible hydrolysis product. The activity of P-glycoprotein in the blood–brain barrier can be assessed only indirectly, by virtue of increased influx to brain of labeled substrates, following administration of P-glycoprotein inhibitors. Positron-emitting inhibitors of phosphodiesterase enzymes have been described, which should herald the eventual development of a much wider array of tracers targeting signal transduction pathways. Cell proliferation can be detected with [11C]-thymidine and synthetic nucleosides. Very recently, it has become possible to measure the abundance in brain of aromatase, which catalyzes the synthesis of estrogen. In general, the net influx of an enzyme substrate from blood to brain is calculated by linear graphical analysis, whereas individual steps in the non-uptake process can be estimated by compartmental analysis. When trapping of a PET tracer is catalyzed by the enzymatic step, the magnitude of the corresponding rate constant (k 3; min−1) ranges from the lowest useful limit of 0.01 min−1 (α-[14C]-methyl-l-tryptophan) to >0.1 min−1 (l-[11C]-deprenyl, [11C]PMP). Quantification is problematic at the lower end of this range due to low specific signal and also at the high end due to blood flow limiting effects.

Key words

Positron emission tomography Methionine FDG FDOPA DOPA decarboxylase Monoamine oxidase Serotonin Acetylcholinesterase Phosphodiesterase Proliferation Aromatase 

1 Introduction

Louis Pasteur at first attributed the transformation of sugar to ethanol to a form of vitalism inherent in living yeast cells. However, work conducted by Eduard Buchner at the University of Berlin demonstrated that extracts of yeast cells could bring about the same chemical transformation; his discovery of cell-free fermentation was recognized by the 1907 Nobel Prize in Chemistry. The chemical nature of the biological catalysts underlying fermentation and other reactions was uncertain, until the successful isolation and crystallization of urease was accomplished by the American chemist James B. Sumner. His demonstration that pure urease was a protein led to a shared Nobel Prize in 1946. In the latter part of the twentieth century, enzymology profited from the advent of improved methods of purification, X-ray crystallography, sequencing and site-directed mutagenesis, among many other molecular biological techniques.

Enzymatic catalysis entails the binding of one or more substrates to specific domains of the enzyme, followed by a thermodynamically favored chemical reaction, sometimes driven by the expenditure of an ATP molecule or other co-substrates. The reaction is followed by the release of the enzymatic products into the medium. The assay of the activity of an enzyme in vitro consists of measuring the rate of product formation at a given substrate concentration. This can entail using some physical or chemical property of the product, such as optical rotation, ultraviolet absorption, or fluorescence as the basis of an assay. In other cases, it may be necessary to separate chemically the product from the reaction mixture using chromatography or some extraction procedure, or by trapping of a gaseous radioactive product, as in the case of classical assays of decarboxylase enzymes. In the crucible of the living brain, these procedures cannot be employed. Rather, the assay of an enzyme activity is based upon a dynamic positron emission tomography (PET) recording of the brain concentration of a radioactive substrate together with that of the radioactive product of the given enzymatic reaction. In general, the rate of enzymatic conversion of the substrate in living brain is deduced by consideration of a compartmental model of tracer uptake relative to a known input from arterial blood. This review presents a synopsis of the state of development of PET procedures for assaying enzyme activity or abundance in living brain. Indeed, there is a relative paucity of radiotracers specifically targeting enzymes, in comparison to the great diversity of receptor ligands. In the course of this review, it will become apparent that PET procedures are most suited for relatively few cases in which the rate of reaction is high, but not too high. More often, enzyme abundance (as distinct from activity) can be measured using positron-emitting inhibitors, which bind reversibly to the target molecule, in the manner of a receptor–ligand interaction (130), but without being substrates for the enzymatic process under consideration.

2 Protein Synthesis

One of the first molecular imaging agents for PET was the amino acid l-[11C]-methionine, obtained by N-[11C]methylation of homocysteine (1). Following intravenous injection of l-[11C]-methionine, serial PET recordings reveal a substantial uptake of radioactivity into pancreas, brain, and other organs. The facilitated diffusion of the essential amino acid methionine across the blood–brain barrier, along with branched chain and aromatic amino acids, is mediated by the leucine-favoring (L1-type) amino acid transporter (2). Once in living brain cells, l-[11C]-methionine binds to transfer-RNA and is then incorporated into proteins, by a process which is irreversibly relative to the 20 min half-life of the radionuclide. As such, l-[11C]-methionine is the prototypic tracer for brain protein synthesis.

The general scheme for kinetic analysis of radiotracers with reversible or irreversible binding is indicated in Fig. 1a. In the present context, the unidirectional influx of l-[11C]-methionine to brain, a facilitated diffusion process, is expressed as K 1, which has the same unit as cerebral blood flow (ml g−1 min−1). The PET tracer l-[11C]-methionine, along with endogenous l-methionine, together occupy an unbound compartment, and are vulnerable to diffusion back into the circulation (k 2; min−1), unless it as bound into protein at rate constant k 3; the magnitude of this rate constant for l-[11C]methionine was 0.06 min−1 in cerebral cortex of healthy subjects (3), to be compared with an estimate of 0.03 min−1 based upon chemical separation of l-[3H]-tyrosine from its metabolites formed in the brain of living rat (4). Defined in these terms, the brain concentration of l-[11C]-methionine at equilibrium could be expressed as K 1/ (k 2 + k 3). This distribution also predicts the partitioning of natural l-methionine across the blood–brain barrier, such that the rate of incorporation for l-methionine into brain protein would be equal to the product of the concentration of l-methionine in plasma and the term K 1 k 3 / (k 2 + k 3), i.e., the net blood–brain clearance as defined below for the case of [18F]-fluoro-deoxyglucose (FDG). This model generally assumes the absence of alternate metabolic pathways in brain, but compartmental analysis of l-[11C]-leucine uptake in human brain also considered kinetic terms for transamination and decarboxylation of the tracer in human brain (5). Furthermore, the interpretation of PET studies with amino acids is made more complicated by the presence of a second source of nonradioactive precursors, which are generated in situ by proteolysis of the reservoir of brain proteins and potentially from amino acid salvage pathways in living brain. Thus, a labeled amino acid arriving from circulation is diluted by a pool of endogenous amino acid, not itself derived from the circulation. In the case of l-[11C]-leucine PET studies of human brain, the fraction of the precursor pool derived from circulation, designated λ, was approximately 0.75 (5), from which could be calculated the “true” rate of incorporation of leucine into brain protein. Failure to include the λ term in the model for kinetic analysis will lead to underestimation of the true rate of protein synthesis. A parametric image showing the entry of l-[11C]-leucine into brain protein reveals fairly uniform trapping throughout the cortical mantle but relatively low trapping in the basal ganglia and white matter (Fig. 1b).
Fig. 1.

(a) The general compartmental model used for analysis of reversibly and irreversibly binding ligands and for enzyme substrates. Tracer in the blood compartment is reversibly transferred across the blood–brain barrier (K 1, k 2). The symbol ⊗ indicates a transporter in the capillary endothelium, i.e., facilitated diffusion transporter for amino acids or glucose, or active transport by P-glycoprotein. The upper part of the figure shows a binding compartment, where tracer is metabolically trapped (k 3) or reversibly bound to the enzyme (k 3, k 4). (b) A parametric mapping showing the rate of incorporation of l-[11C]-leucine into brain protein (image courtesy of Dr. Carolyn Beebe Smith, Section on Neuroadaptation and Protein Metabolism, National Institute of Mental Health, Bethesda, MD, USA). (c) The chemical structure of FDG and (d) its uptake in a series of horizontal planes in a patient with typical Alzheimer’s disease, and (e) the surface projections and t-statistic maps of the same patients, revealing bilateral parietal hypometabolism. (f) A times series of emission images obtained with the DOPA decarboxylase substrate FDOPA and (g) the corresponding parametric map showing the net influx to brain (images courtesy of Dr. Jan Kalbitzer and Prof. Andreas Heinz, Charite). (h) The net influx to brain of the tryptophan hydroxylase substrate α-[11C]-methyl-l-tryptophan in (left) a patient experiencing a migraine attack and (right) the same patient after treatment with sumatriptan (figure courtesy of Professor Mirko Diksic, Montreal Neurological Institute). (i) The distribution of MAO-A revealed by [11C]-harmine and (j) the distribution of PDE4 revealed by [11C]-(R)-rolipram (both courtesy of the CAMH PET Centre, Toronto).

PET with l-[11C]-methionine has been extensively used in neuro-oncology, based upon the relatively rapid protein synthesis inherent to most tumors. In an early clinical application, l-[11C]-methionine uptake correlated with histological grade of glial tumors and declined in two patients following radiotherapy (6). The use and limitations of l-[11C]-methionine PET in the clinical management of gliomas has recently been reviewed (7).

In theory, any of the 21 natural amino acids could serve as a tracer for protein synthesis. However, the process selectivity of a given amino acid tracer is reduced by the extent of alternate metabolic pathways, in addition to protein synthesis. In a study of l-[3H]-methionine incorporation in a human astrocytoma line, 55 % of the radioactivity was in the protein fraction, whereas 11 % was incorporated into RNA and a lesser fraction in lipids after 2 h incubation (8). Thus, the entire trapping of labeled l-methionine in brain cannot be exclusively attributed to protein synthesis, just as in the case for l-[11C]-leucine described above. The multiplicity of metabolic fates for l-[11C]-methionine is also evident in radiochromatograms of human plasma extracts, which revealed at least three labeled metabolites, including l-[11C]-serine, which could constitute a second input to brain protein synthesis (9). Whereas l-[14C]-methionine gives rise to transmethylation products via the intermediate of S-adenosyl-l-[14C]-methionine, carboxylic acid labeling is metabolically more restrictive, giving rise only to [14C]-CO2, which is rapidly eliminated from brain (10); in either case, nonprotein synthesis pathways cannot be entirely neglected from the model. The distribution of l-[1-14C]-tyrosine (i.e., the carboxymethyl label) in tumor bearing rats showed a more favorable specificity, with 80 % of tissue radioactivity bound to protein after 1 h (11). A similar fraction of protein labeling was obtained in mice with the synthetic amino acid tracer l-[2-18F]-fluorotyrosine (12). However, in human PET studies, increased influx of l-[2-18F]-fluorotyrosine into tumors proved to be driven by uptake (i.e., amino acid transport), whereas the rate of incorporation into the tumor proteins was actually reduced (13).

In a rat autoradiographic study based on brain uptake of l-[14C]-leucine, protein synthesis was globally increased during slow wave sleep, suggesting a restorative function of sleep (14). An analysis of brain uptake of l-[14C]-leucine, with proper consideration of leucine recycling, indicated a 10–20 % decline in cerebral protein synthesis in aged rats (15). Despite these preclinical findings, there have been relatively few non-oncological studies of protein synthesis in human brain; in one such l-[11C]-methionine PET study, there was a 20 % reduction in the magnitude of k 3 in gray matter of patients with Alzheimer’s disease (3). Using l-[11C]-tyrosine, an inverse relationship was found between plasma phenylalanine levels and brain protein synthesis in human patients with phenylketonuria, consistent with substrate limitation due to competition for blood–brain barrier transport (16). In an l-[11C]-leucine PET study of healthy volunteers, propofol anesthesia was without effect on the magnitude of λ or on the rate of protein synthesis in brain (17).

3 Hexokinase and the Cerebrometabolic Rate for Glucose

Evidence obtained from cortical slice preparations suggests that brain can utilize hydroxybutyrate as an alternate substrate for oxidative phosphorylation (18). While this pathway may be significant during condition of ketosis, as occurs during starvation, the healthy brain is generally considered to have an absolute dependence on glucose to meet its substantial demand for ATP production. PET studies in the anesthetized pig indicate that the rate of oxygen consumption exceeds that of glucose by a factor of 6, exactly as expected from the stoichiometry for the complete oxidation of glucose (19). The cerebrometabolic rate for glucose (CMRglc) in rat brain has been measured using [14C]-glucose labeled in position six, although the model for analysis must accommodate the rapid elimination of [14C]-CO2 from brain (20); this method has not been extended for brain PET studies with 6-[11C]-glucose. Instead, PET methods for measuring CMRglc have been based upon the classic compartmental analysis for the trapping in brain of 2-[14C]-deoxyglucose (21). The compartmental model for deoxyglucose and its extension for PET studies with FDG in human brain (22) will be reviewed in detail presented elsewhere in this volume. In brief, kinetics of FDG uptake bares a formal resemblance to the schematic for amino acid influx, described above. Here, the initial phase of the cerebral uptake of glucose tracers is mediated by a specific glucose transporter in the blood–brain barrier, which is permissive to a saturable facilitated diffusion of its several substrates between blood and brain. In direct analogy to the case for labeled amino acids presented above, this process can be expressed kinetically as an influx (K 1; ml g−1 min−1) and an efflux diffusion rate (k 2; min−1), with the process of main interest being the activity of hexokinase with respect to FDG in living brain (k 3; min−1). The mean magnitude of k 3 in gray matter of human brain was close to 0.06 min−1 (22).

While [14C]-deoxyglucose and FDG are adequate substrates for the glucose transporter and are phosphorylated in brain by the activity of hexokinase, the corresponding phosphorylated substrates do not proceed further in the anaerobic respiratory pathway. Furthermore, the phosphorylation step is approximately irreversible. In fact, some dephosphorylation of FDG occurs in living brain, but at a rate (k 4; min−1) one tenth that of the hexokinase step (22). The contribution of k 4, which lead to underestimation of the true magnitude k 3, can usually be neglected without great peril, since it has little effect on the observed brain radioactivity concentrations measured during 60 min FDG-PET recordings.

Brain glycogen constitutes an additional precursor pool for glucose, which might be compared to the problem of amino acid recycling in the estimation of protein synthesis rate, noted above. However, the content of glucose (as glycogen) in rat cerebral cortex is reported to be 50 μmol hg−1 (23). This reservoir could sustain brain glycolysis for just about 1 min. While brain glycogen reserves may contribute to sustaining certain kinds of phasic metabolic demands, the mass involved should not have any effect on the quantitation of CMRglc with FDG.

In most quantitative FDG studies of CMRglc, the magnitudes of K 1, k 2, k 3 (and k 4) are not determined separately, but are collapsed into a single quantity describing the net influx of plasma FDG into brain (K in), which is defined as (K 1 × k 3) / (k 2 + k 3), just as in the case for protein synthesis, cited above. The magnitude of K in can be calculated as a simple linear regression analysis, knowing only the time-series of the total radioactivity concentrations in brain (measured by PET) and the arterial blood input (24, 25). The measurement of the FDG input is simpler than in the case for labeled amino acids (and indeed, most every PET tracer), due to the near absence of labeled metabolites in blood. Thus, the whole blood radioactivity can be used as the input, without any need for fractionation or extraction. However, the requirement for serial arterial sampling is still onerous and is only used for specific research protocols, rather than in clinical investigations. For most clinical purposes, a single image recorded at 45–60 min after the FDG injection serves as a useful surrogate for the kinetic estimates described above. There are nearly 40,000 published reports on FDG, the great preponderance of which are clinical oncology studies; almost all tumors take up FDG faster than do most healthy tissues.

Nonetheless, FDG-PET is of limited use for detecting brain tumors, because of the very high overall brain uptake. However, it has great utility for mapping the pathophysiology of neurodegenerative disease. One of its first clinical applications revealed decreased cerebral FDG uptake among patients with suspected Alzheimer’s disease (AD), correlating with the extent of cognitive impairment (26). In a widely used diagnostic method, the FDG uptake in an individual is presented as a surface projection, and the deviation from the expected pattern on normal subjects is calculated as a pixel-wise Z-statistic (27); this procedure gives diagnosis of AD with almost perfect sensitivity and specificity. A representative case is presented in Fig. 1d in which the typical parietal hypometabolism of AD is clearly evident. In the absence of kinetic analysis, the FDG accumulation in individual brains can be quite variable due to differences in plasma glucose levels and other factors. Consequently, statistical comparisons are usually made after scaling of the intensity maps to the global tracer uptake, to some reference tissue, assumed to be unaffected by disease. If this assumption is violated, the scaling procedure can lead to spurious apparent increases in the relative FDG uptake in some brain structures (28). Data-driven extraction of reference clusters (29) seems more suited for detecting real signals in non-quantitative PET studies (30). Routine procedures for AD diagnosis present results for a number of alternate normalizations, so as to minimize the risk of spurious findings (Fig. 1e).

However, useful as a diagnostic tool, statistical approaches with data normalization may not capture individual aspects of the disease; considerable variability in the pattern of hypometabolism can occur within populations meeting the diagnostic criteria for AD (31). The typical pattern of decreased FDG uptake in the brain of AD patients overlaps with, but is not identical to, the distribution of amyloid as revealed by carbon-11 labeled Pittsburgh Compound B (32), indicating that decreased energy metabolism in brain is not entirely defined by the local deposition of amyloid, but may occur in the manner of a functional denervation syndrome. A remarkable study with follow-up during more than 10 years suggests that decreased FDG uptake long-proceeds the onset of clinically significant cognitive changes (33).

4 DOPA Decarboxylase

The development and testing of the synthetic DOPA decarboxylase substrate 6-[18F]-fluoro-3,4-dihydroxyphenyl-l-alanine (FDOPA) was an early success of molecular brain imaging by PET (34). FDOPA in circulation is transferred across the blood–brain barrier by facilitated diffusion mediated by the common carrier of large neutral amino acids. As such, FDOPA influx to brain is inhibited by competition from many other amino acids (35), and FDOPA scans are therefore best conducted in a fasting condition. FDOPA is a good substrate for the enzyme DOPA decarboxylase (36) in nigrostriatal dopamine fibers, which entrap the product 6-[18F]-fluorodopamine in synaptic vesicles (37). As such, the analysis of FDOPA uptake in brain has a formal resemblance to the case of FDG, in that it could be described in terms of K 1, k 2, and k 3 relative to a defined arterial input.

However, the interpretation of FDOPA-PET images is complicated by several factors, which are considered in detail in a recent review (38). FDOPA is a substrate for catechol-O-methyltransferase, irrespective of the position in the aromatic ring of the fluorination (39), such that substantial amounts of the inert product O-methyl-FDOPA (OMFD) accumulate in plasma of subjects during FDOPA-PET recordings (40). This product passes into brain by the common transporter of large amino acids, contributing a significant nonspecific signal to all brain regions, which increases with time (41, 42). Furthermore, [18F]-fluorodopamine is not perfectly trapped in living brain, but is slowly decomposed by monoamine oxidase (43) resulting in progressive loss of specific signal (44) due to washout of the diffusible acidic metabolites. Finally, FDOPA lacks perfect neurochemical specificity; while most brain DOPA decarboxylase occurs in dopamine fibers, metabolism in serotonin neurons contributes to part of the PET signal (45).

Despite these formal complexities and ambiguities, FDOPA remains one of the most widely used tracers for PET studies of brain physiology. This is due to its indisputable sensitivity for detecting nigrostriatal degeneration of Parkinson’s disease (PD) and related disorders. The time course of FDOPA uptake in a healthy individual reveals the phases of distribution and binding; the initial phase of blood–brain transfer is followed by trapping in striatum and washout of radioactivity from non-binding regions such as the cerebellum (Fig. 1f). The net influx of FDOPA to brain relative to the arterial input is frequently calculated by graphical analysis as \( K_{\rm{in}}^{\rm{app}} \) (Fig. 1g), which has units of cerebral blood flow, in direct analogy to the cases for [11C]-methionine and FDG described above, with the key mechanistic difference that the endogenous substrate (l-DOPA) is normally synthesized in situ rather than entering from circulation. As such, FDOPA-PET reveals the capacity for dopamine synthesis from exogenous l-DOPA rather than the actual rate of endogenous synthesis.

The corresponding rate constants for FDOPA metabolism can be calculated with compartmental modeling, which indicates that the DOPA decarboxylase activity relative to FDOPA (\( k_3^D \)) is close to 0.1 min−1 in healthy putamen (44, 46) and is reduced by one half in PD patients (47). Due to the considerable difficulties in the compartmental modeling approach, FDOPA utilization is frequently calculated as the net influx (\( K_{\rm{in}}^{\rm{app}} \)) described above, which is directly analogous to the linear graphical analysis of FDG uptake. For more routine clinical applications, a noninvasive reference tissue method serves adequately for the diagnosis of nigrostriatal degeneration. This semiquantitative approach has revealed subclinical degeneration in a kindred with hereditary Lewy body PD (48), the rate of neurochemical progression during longitudinal examination of idiopathic PD (49), and the possible attenuation of the rate of progression through treatment with a dopamine agonist (50). The use of FDOPA-PET for discriminative diagnosis of PD and a number of other disorders of the basal ganglia is reviewed elsewhere (38).

Increased capacity for dopamine synthesis in striatum of patients with schizophrenia was reported in an early FDOPA-PET study (51); this finding has been replicated in a number of subsequent reports, including one employing the alternate DOPA decarboxylase substrate l-[11C]-DOPA (52). Others have found that not only is the rate of [18F]-fluorodopamine increased in patients with schizophrenia but the rate of washout is also higher than normal (53), resulting in a neurochemical circumstance which was described as poverty in the midst of plenty due to the poor retention of [18F]-fluorodopamine in a vesicular compartment.

5 Tryptophan Hydroxylase

Major motor symptoms of PD are attributable to the primary nigrostriatal degeneration and are alleviated by dopamine agonists, but neuropsychiatric disease are not so clearly linked to serotonin systems. Despite the wide acceptance of a serotonin hypothesis of depression, the pathophysiology of depression is poorly established and could profitably be investigated with appropriate PET tracers. Presynaptic serotonin synthesis can be probed with 5-hydroxy-[11C]-l-tryptophan (54), but with some ambiguity arising from the imperfect selectivity for DOPA decarboxylase in serotonin versus dopamine neurons. An alternate and more direct method for measuring serotonin synthesis in living brain has been presented by the synthetic amino acid α-[14C]-methyl-l-tryptophan, which is entrapped in the dorsal raphe nucleus and in serotonin terminals of living rat (55); Like the other amino acids mentioned in this chapter, α-[14C]-methyl-l-tryptophan is reversibly transferred across the blood–brain barrier and is potentially a substrate for tryptophan hydroxylase, the rate-limiting step for serotonin synthesis. Unlike natural l-tryptophan, this substance is not a substrate for protein synthesis, which would otherwise present a very high global trapping, thus obscuring any specific signal related to neurotransmitter synthesis. The rate of conversion of α-[14C]-methyl-l-tryptophan is slow in vivo, and the sensitivity of the corresponding PET tracer α-[11C]-methyl-l-tryptophan has been called into question (56). However, others find a good correlation between the next influx of α-[11C]-methyl-l-tryptophan and that of DOPA decarboxylase substrate 5-hydroxy-[11C]-l-tryptophan (54), and a high correlation with postmortem serotonin concentrations (57). Compartmental analysis of α-[14C]-methyl-l-tryptophan uptake in human brain gives magnitudes of k 3 (the rate constant for irreversible trapping) in the range of 0.01–0.02 min−1 (58), which is lower than for the other enzyme substrates discussed in this chapter.

Representative parametric images of serotonin synthesis in human brain, calculated as a net tracer influx, are presented in Fig. 1h. The left-most image shows the condition during a spontaneous migraine attack, whereas the image to the right shows the same patient during treatment with sumatriptan; the global reduction is consistent with an agonist action of the drug at autoreceptors on serotonin neurons and terminals (59). Cortical foci of increased α-[11C]-methyl-l-tryptophan are frequently associated with epileptogenic dysplasia in children with tuberous sclerosis (60) and can potentially guide the planning of surgical resection, especially in cases characterized by interictal spiking (61).

Parametric mapping procedures with α-[11C]-methyl-l-tryptophan have revealed focal cortical reductions in patients with major depression (62) and in suicide attempters (63). In another study, stimulation of α-[11C]-methyl-l-tryptophan influx to the prefrontal cortex in depressed patients treated with a serotonin selective reuptake inhibitor was augmented by co-treatment with an antagonist of autoreceptors on serotonin neurons (64), consistent with a theory predicting synergistic action of the two medications in the treatment of depression.

6 Monoamine Oxidase

The ubiquitous enzyme for oxidative deamination of biogenic amines occurs in two distinct forms with somewhat differing substrate specificities, whereas MAO-A prefers serotonin and noradrenaline and MAO-B prefers β-phenylethylamine and the neurotoxin MPTP, both enzymes catalyze the deamination of dopamine and tryptamine (65). As such, MAOs are important targets for molecular imaging of monoaminergic systems; in brain, MAO-A is most highly expressed in noradrenaline neurons (65), while MAO-B is most abundant in serotonin neurons and in the tuberomammillary histamine neurons (66). The binding of reversible MAO inhibitors potentially gives information about the abundance (B max) of the enzyme in brain, but an important class of irreversible inhibitors, the suicide substrates, are trapped by an irreversible binding process at a rate determined by actual catalytic activity (V max).

The first PET tracer for MAO was the MAO-B substrate [11C]MPTP, which proved to accumulate in the striatum of rhesus monkey, apparently by the same enzymatic trapping mechanism underlying the notorious toxicity of that compound for dopamine neurons (67, 68). More promising for human studies were the suicide substrates for MAO-A ([11C]-clorgyline) and MAO-B ([11C]-deprenyl), which were trapped in human brain in a stereoselective manner (69). Consistent with mechanistic understanding of the reaction of these MAO suicide substrates, α-deuterated [11C]-deprenyl ([11C]-deprenyl-D2) reacted in brain with a substantial isotope effect (70), which proved to present an advantage for calculating k 3, the rate constant corresponding to MAO-B activity in living brain; ordinary [11C]-deprenyl reacts so quickly (k 3; 0.11 min−1) that it was difficult to separate the parameter of interest from tracer delivery from blood, i.e., K 1 (71), whereas the corresponding rate constant for [11C]-deprenyl-D2 was a more temperate 0.03 min−1. In an early clinical application of [11C]-deprenyl-D2, tracer binding was enhanced in the vicinity of epileptic foci of the human temporal lobe, presumably reflecting MAO-B in reactive astrocytes (72). The isotope effect proved less useful for the case of [11C]-clorgyline, due to the emergence of a non-MAO-A binding component in white matter (73).

The binding of MAO ligands and substrates should be vulnerable to competition from other inhibitors or substrates. Thus, [11C]-harmine, which binds reversibly to MAO-A in vitro with an affinity of 2 nM (74), has been used in human PET studies for assessment of the central inhibition of MAO-A (75). Likewise, [11C]-deprenyl-D2 has been used in a competition paradigm to test the extent of occupancy of a novel drug at MAO-B sites in human brain (76). The discovery of reduced MAO-B activity in brain and peripheral organs of smokers suggests the presence of a potent inhibitor in tobacco smoke (77). The inhibition must be cumulative, since smoking a single cigarette was without effect on [11C]-deprenyl-D2 binding (78). Inhibition of MAO-A was revealed in brain of smokers in a PET study with [11C]-clorgyline (79), which was recently confirmed in a study with the reversible MAO-A ligand [11C]-beflaxatone (80). It remains to be established how MAO inhibition might contribute to the psychopharmacology of tobacco; nearly complete inhibition of MAO failed to evoke any potentiation in the reactivity of dopamine release to amphetamine challenge in [11C]raclopride PET studies of rat (81) or pig (82).

PET with [11C]-harmine shows MAO-A to be concentrated in the midbrain and striatum, with lesser activity in the insular cortex (Fig. 1i). Globally increased [11C]-harmine uptake in brain has been described in untreated, non-smoking patients with depression (83), and persistence of this increase following treatment is reported to predict for relapse (84). Increased [11C]-harmine uptake, presumably of a transient nature, is also described in women in the early postpartum period (85).

While [11C]-harmine shows excellent properties as a reversible MAO-A ligand, a reversible ligand with selectivity for MAO-B imaging has remained elusive. Such a compound would surely be of use for clinical investigation of Parkinson’s disease, in which MAO-B has been implicated, based upon the MAO-B-catalyzed toxicity of MPTP for dopamine neurons. The reversible and selective MAO-B inhibitor Ro 19-6327 was successfully radiolabeled by replacing the chlorine with 123I [Ro 43-0463] (86) or 18F, and both tracers were evaluated in human subjects (87). While [123I]-Ro 430463 had appropriate properties for SPECT imaging, the 18F-analog had limited brain uptake. More recently, two carbon-11 labeled oxazolidinone derivatives have been reported by the Orsay PET group as highly promising reversibly binding MAO-B radiotracers: [11C]-MD-230254 (88) and [11C]-SL25.1188 (89). Both radiotracers proved to enter brain and obtain reversible specific binding in nonhuman primate brain, which could be displaced by l-deprenyl treatment. High binding was present in the thalamus and striatum, and moderate binding in the cerebellum, which would preclude its use as a reference tissue. As both of these compounds are obtained via the specialized labeling agent [11C]-phosgene, their use is currently restricted to only a few laboratories.

7 Acetylcholine Esterase

A number of populations of acetylcholine neurons are present in brain, including the large interneurons of the striatum and the cortically projecting neurons of the basal forebrain; this latter population is of particular interest due to its degeneration in AD. Developing a PET assay for the synthesis of acetylcholine would be problematic due to the ubiquity of the precursors, acetate and choline. However, there are a number of PET methods for detecting acetylcholine esterase (AChE), the enzyme decomposing acetylcholine. Early efforts focused on AChE inhibitor ligands, such as [11C]-physostigmine (90), [11C]-methyltacrine (91), and [11C]-donezepil (92). PET studies with these inhibitors, which are indicators of B max, have mostly been supplanted by a series of esters based on N-[11C]-methylpiperdin-4-yl propionate ([11C]-PMP), where the metabolite is formed in brain at a rate dependent upon the AChE activity and is retained due to its considerable lipophilicity (93). An unconstrained fitting of K 1, k 2, and k 3 (the AChE activity) proved to be suited for human brain regions of low AChE activity, but certain constraints were required for adequate fitting in striatum and other regions of high activity (94); the magnitude of k 3 ranged from 0.02 min−1 in cerebral cortex to 0.15 min−1 in striatum, where the coefficient of variance was very high. As such, compartmental analysis of this tracer is not reliable in brain regions of highest AChE activity, in analogy to the case of [11C]-deprenyl, mentioned above. However, a relatively simple “shape analysis” of the [11C]-PMP time–activity curves provides reasonable estimates of k 3 without the necessity of arterial sampling for compartmental analysis (95), whereas others have estimated k 3 non-invasively in extrastriatal regions using a method based upon the very substantial trapping of tracer in striatum (96).

PET studies with [11C]-PMP showed stability of AChE activity with normal aging (97) and revealed a 30–40 % reduction in the temporal and parietal cortex of patients with AD (98). The IC50 of donezepil for blocking AChE in the brain of monkey has been estimated relative to observations of [11C]-PMP uptake (99); analogous studies in patients revealed a 30–40 % blockade of AChE in AD patients treated with donezepil (100) or rivastigmine (101). In a remarkable study in awake monkeys, treatment with donezepil increased acetylcholine levels in microdialysis samples from cortex, while decreasing [11C]-PMP uptake, and likewise decreasing the binding in cerebral cortex of a PET ligand for muscarinic acetylcholine receptors (102). However, persistent 30–40 % blockade of [11C]-PMP trapping did not influence the binding of [11C]-nicotine at nicotinic receptors in cerebral cortex of AD patients treated with galantamine (103).

A study in early AD patients suggested that cortical and amygdala reductions in AChE activity precede measurable reductions in the basal forebrain, i.e., the location of the ascending cholinergic neurons (104). However, interpretation of results with AChE ligands is uncertain, since the cortical activity need not have a simple functional relationship with the state of degeneration of the cortically projecting cholinergic neurons. On the other hand, secretion of the “read through” variant of AChE into the cerebral spinal fluid may be stimulated by galantamine treatment, without alterations in the secretion of the synaptic variant; [11C]-PMP-PET cannot distinguish these forms of the enzyme (105). Matters are more complicated by the occurrence in brain of a distinct acetylcholine-hydrolyzing enzyme, butyrylcholinesterase, which can be detected in PET studies with the more selective substrate 1-[11C]-methyl-4-piperidinyl n-butyrate ([11C]-MP4B) (106). Butyrocholinesterase activity may be increased in AD patients, especially those with the ApoE ε4 allele (107); since acetylcholine is also a substrate for butyrocholinesterase, high levels of the latter enzyme may predict for poor response to selective AChE inhibitors.

8 P-Glycoprotein

The P-glycoprotein is an ATP binding cassette protein, which is the product of the multidrug resistance gene. Highly expressed in certain tumor lines, it is also constitutively resident in the brain capillary epithelium, where its ATP-dependent activity contributes to the selective permeability of the blood–brain barrier. The very broad substrate specificity of P-glycoprotein is evidenced in PET studies with [11C]-labeled alkaloids, antineoplastic agents, and receptor ligands (108), all of which may be substantially extruded from brain.

The first PET tracers proposed specifically for probing P-glycoprotein have been substrates such as [11C]-verapamil, the cerebral uptake of which is enhanced in P-glycoprotein knockout mice and upon treatment with cyclosporine A, an inhibitor of P-glycoprotein activity (109). Functional differences between several haplotypes of P-glycoprotein were not evident in a [11C]-verapamil PET study of human brain (110). Using the [11C]-verapamil V D (K 1/k 2) as a surrogate inverse marker for P-glycoprotein activity (higher activity gives lower V D ), decreased P-glycoprotein activity could be detected as a function of normal aging (111). Decreased activity was also noted with the progression of Parkinson’s disease and some other basal ganglia disorders (112); these observations may suggest a mechanism for greater vulnerability of the aging nervous system to toxic processes and may have particular implications for Alzheimer’s disease, given that the soluble beta-amyloid is a natural substrate of P-glycoprotein (113).

Observations in experimental animals have predicted an upregulation of P-glycoprotein in association with seizure disorders, to an extent that may reduce the efficacy of anticonvulsant drugs, some of which are also P-glycoprotein substrates. However, a pilot study failed to reveal any significant asymmetry in [11C]-verapamil kinetics between healthy subjects and patients with temporal lobe epilepsy (114). Using a shift assay with the serotonin 1A ligand and P-glycoprotein substrate [18F]-MPPF, P-glycoprotein activity can be assessed indirectly through increases in the magnitude of K 1 following treatment with tariquidar, a new generation P-glycoprotein inhibitor (115). This approach revealed globally elevated P-glycoprotein in the brain of epileptic rats with documented pharmacoresistance (116).

Alternate PET tracers which are the substrates for P-glycoprotein include the substrate [11C]-N-desmethyl-loperamide (117), and [11C]-tarquidar, although it remains uncertain if this compound is a true substrate, or a non-competitive inhibitor (118). The ideal P-glycoprotein tracer would yield estimates of transport rate, uncontaminated by the passive diffusion of tracer across the blood–brain barrier; a suitably labeled prodrug and substrate formed within brain might give more direct indication of the catalytic activity of P-glycoprotein than is afforded by simple inhibitors.

9 Phosphodiesterase

The great majority of available PET tracers target cell surface receptors, and there has been relatively little investigation of signal transduction pathways. Intracellular signaling of GTP-protein-binding receptors, which includes most of the receptors of dopamine, serotonin, and other biogenic amines, is mediated by intracellular levels of the cyclic nucleotides 3′,5′-cyclic adenosine monophosphate (cAMP) and cyclic guanosine monophosphate (cGMP). The phosphodiester bonds in these compounds are hydrolyzed by members of a large family of phosphodiesterase (PDE) enzymes, which are classified into 11 families (PDE1–PDE11). Further sub-categorization of these enzyme families includes subfamilies of genes as well as a splice variants derived from a single gene. The state of development of molecular imaging of PDEs and other enzymes involved in signal transduction is in its infancy. A representative PET image obtained with the PD4 ligand [11C]-rolipram is illustrated in Fig. 1j. The properties of this ligand and of a number of other ligands targeting signaling pathways are reviewed in (130).

10 Cell Proliferation and Thymidine Kinase

Nucleotide synthesis in dividing cells could be detected with [11C-]thymidine, but this tracer was subject to rapid metabolism in vivo (119); a better PET tracer would have a more constrained metabolism, in analogy to the case of FDG. To this end, the synthetic nucleoside 3′-deoxy-3′-[18F]-fluorothymidine (FLT) was developed as a tracer of cell proliferation, especially in healthy bone marrow and in solid tumors (120). The basis of its entrapment is its phosphorylation by a specific thymidine kinase that is mainly expressed in dividing cells. Like FDG-phosphate, FLT-phosphate does not proceed farther in the metabolic pathway. FLT is as sensitive as FDG for the detection of gliomas; detection of an acute metabolic response with FLT-PET was predictive of survival in patients treated for recurrent gliomas (121). Net influx (K in) maps for FLT relative to the arterial input gave a sensitive indication of the proliferative zone in an astrocytoma, with much less background uptake that was seen with [11C]-methionine; a more detailed kinetic analysis of dynamic FLT recordings could be used to evaluate the relative activity of the thymidine kinase (k 3; circa 0.05 min−1) in brain tumors, and suggested the presence of a slow dephosphorylation of the tracer (k 4), again in analogy to FDG-PET (122).

A thymidine kinase from herpes simplex virus in conjunction with a synthetic substrate such as 5-[124I]iodo-2′-fluoro-2′deoxy-1-beta-d-arabino-furanosyl-uracil (FIAU) has been proposed as a reporter for detecting transfection in experimental gene therapy (123). Corresponding PET studies in tumor bearing mice have delineated the tumors expressing the viral gene (124), but this promising technique has not yet been applied in humans.

11 Aromatase

Aromatase is the product of the CYP19A1 gene, which catalyzes the formation of estradiol from testosterone, and likewise the formation of estriol and estrone from other androgen precursors. It has a ubiquitous distribution throughout the body and is expressed in a number of cell populations in brain, including pyramidal cells in the cerebral cortex, specific groups of neurons in the hippocampus, and likewise in cortical astrocytes (125). Estrogen has particular roles in neuroendocrine function and establishing sexual dimorphism of the mammalian brain and is also thought to mediate synaptogenesis and neuronal survival. A number of transcripts of the single aromatase gene are differentially expressed in different brain regions (126). Very recently, it has become possible to visualize the cerebral distribution of aromatase with [11C]-vorozole, a synthetic enzyme inhibitor; the highest binding autoradiograms in medial amygdala, the bed nucleus of stria terminalis, and the preoptic area of male rat brain and to a lesser extent in female rats (127). Abundant displaceable binding of [11C]-vorozole was detected in a PET study of young men, notably in the amygdala, thalamus, medulla, and the preoptic area. A similar pattern was seen in a group of three women, but binding was higher for scans recorded at midcycle, when estrogen levels were higher than when they were rescanned in the menstrual/early follicular phase (128). Intravenous administration of nicotine, at a dose comparable to that encountered in smoking, substantially blocked [11C]-vorozole binding in the brain of baboons (129). This ligand promises to open up whole new domains of research in the neurobiology of addiction, aging, gender differences in brain function, as well as in clinical oncology of estrogen-sensitive tumors.


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Copyright information

© Springer Science+Business Media New York 2012

Authors and Affiliations

  • Paul Cumming
    • 1
  • Neil Vasdev
    • 2
  1. 1.Department of Nuclear MedicineLudwig-Maximilians-Universität MünchenMünchenGermany
  2. 2.Division of Nuclear Medicine and Molecular ImagingMassachusetts General Hospital, Harvard Medical SchoolBostonUSA

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