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Turku PET Centre Modelling report TPCMOD0033 2006-05-26Vesa Oikonen
Analysis of [11C]L-deprenyl-D2 (DEP-D) brain PET studies
Monoamine oxidase B (MAO B) is present in the outer mitochondrial membrane occurring in thebrain predominantly in glial cells and in serotonergic neurons [Fowler et al., 2005]. It oxidizesamines (for example dopamine) from both endogenous and exogenous sources. MAO B isselectively and irreversibly inhibited by L-deprenyl (selegiline). When the enzyme-substratecomplex is formed, the rate-limiting step of MAO B catalyzed oxidation creates a highly reactiveintermediate, which forms a covalent bond with the enzyme, thus irreversibly inactivating it[Fowler et al., 2005]. When L-deprenyl is labelled with 11C, the active enzyme MAO B becomeslabelled, and it can be imaged in vivo
A three-compartment model can be applied to the time-activity curves (TACs) of labelled L-deprenyl in the brain and plasma to estimate MAO B activity in the brain. In the model, K1represents the plasma-to-organ transfer constant, k2 is the transfer rate of radiotracer from organback to plasma, and k3 describes the rate of binding to MAO B. Under the PET study conditions, k3is proportional to the functionally active free enzyme concentration. Because binding is irreversible,it is assumed that k4=0. From these model constants, K1 and k2 are dependent on blood flow, but k3is not. Due to the high extraction of L-deprenyl, K1 is dominated by blood flow instead of capillarypermeability [Fowler et al., 1988, 1995]. Also the net influx rate Ki (=K1*k3/(k2+k3)) is dependenton blood flow [Lammertsma et al., 1991], as well as the more directly radiotracer uptake relatedparameters, like SUV.
The very high rate of binding of labelled L-deprenyl to MAO B creates difficulties in applying themodel. The estimates of k2 and k3 tend to be highly correlated, and the rate of radiotracer binding(k3) and delivery (K1) are hard to separate [Fowler et al., 2005]. Especially in the brain regions ofhigh MAO B concentrations (basal ganglia, thalamus and cingulate gyrus), and in the elderly peoplewho have reduced blood flow, the rate limiting step is the radiotracer delivery instead of binding[Fowler et al., 1993].
To reduce the problem with correlating k2 and k3, a combination model parameter k3 has beenintroduced as an index of MAO B activity; is the K1 over k2 ratio [Fowler et al., 1993 and 1995].
K1 and k2 are both dependent on the blood flow, but and k3 are independent of blood flow.
Because this index contains the ratio k3/k2, the effect of their (positive) correlation is expected to besmaller. Reproducibility in test/retest studies was improved by using k3 instead of k3 [Logan et al.,2000].
The rate-limiting step of MAO B catalyzed oxidation involves cleavage of a certain carbon-hydrogen bond in L-deprenyl. A carbon-deuterium bond is more difficult to cleave than the carbon-
hydrogen bond, which leads to reduced rate of reaction when this hydrogen is substituted withdeuterium (so called deuterium isotope effect). Because the very high binding rate of [11C]L-deprenyl has been found to be problematic in quantification of MAO B activity, the deuterium-substituted L-deprenyl, [11C]L-deprenyl-D2 is therefore preferred as PET radiotracer [Fowler et al.,1988, 1995, 2004].
Unlike most enzymes, MAO B activity ( k3) increases clearly with normal aging, which isaccompanied by decreasing blood flow (K1) [Fowler et al., 1997]. Therefore, the age must becontrolled in the PET studies of MAO B. If the age effect is studied, the measured index of MAO Bactivity must not be flow dependent. The age-related and disease-associated increase of MAO B hasbeen attributed to neuron loss and gliosis (increase in glial cells).
As described above, the tissue uptake of [11C]L-deprenyl-D2 and especially [11C]L-deprenyl isstrongly dependent on blood flow. Therefore, to quantification of MAO B activity, the compartmentmodel and a blood flow independent model parameter or index, like k3 or k3 must be used.
Otherwise, for example, the increase of MAO B activity in epileptogenic region might beunderestimated because of subsequently reduced blood flow.
MAO B is highly and variably inhibited in smokers [Fowler et al., 2003]. An overnight abstinencefor smokers does not produce any recovery of MAO B activity. However, smoking a singlecigarette does not produce a measurable decrease in MAO B activity in non-smokers [Fowler et al.,2003].
In the test-retest setting, Logan et al. (2000) noticed a decrease of K1 in the second scan (-7.7 ±13.2%), although the decrease was not statistically significant (n=5). This may be caused byfamiliarization with the PET procedure and decreased anxiety [Logan et al., 2000].
The brain concentrations of [11C]L-deprenyl-D2 peak at about 5 min after injection, and after awashout phase the concentrations reach a plateau about 30 min after injection [Fowler et al., 1995].
Fowler et al. (1995) subtracted from the PET data an approximate 4% blood volume beforeanalyzing the data using the three-compartment model or graphical analysis for irreversiblesystems.
Lammertsma et al. (1991) included the vascular volume fraction in the model equations, noting thatwhole blood curve must be used instead of (total) plasma curve.
Free fraction in plasma was 6.0% [Fowler et al., 2004]. Considering the high K1 estimates,dissociation rate of the radiotracer from plasma protein may be high, so that most of protein boundradiotracer is also available for transport to the tissue.
For [11C]L-deprenyl, Lammertsma et al. measured the blood-to-plasma ratio from discrete samplesbetween 5 and 90 min. Based on in vitro experiments, they assumed that the plasma-to-blood ratiois 1.126 at the time of the arrival of the tracer in the blood, taken to be the time where the bloodcurve increased above 1% of the peak value [Lammertsma et al., 1991]. They fitted a multi-exponential function to the ratios, determining the number of exponentials based on AIC and SC.
The multi-exponential function was then used to calculate the total plasma curve from arterial bloodcurve which had been measured on-line.
Fowler and Logan et al. do not give details on this transformation in their publications.
For [11C]L-deprenyl, Lammertsma et al. measured the fraction of plasma metabolites from foursamples at 5, 10, 15 and 20 min, and fitted a single exponential function to the fractions, assumingno metabolites at time 0. The exponential function was used to calculate the concentration ofunchanged tracer in the plasma.
Fowler and Logan et al. do not give details on this correction in their publications.
Lammertsma et al. (1991) corrected for the time delay between blood curve and whole brain PETdata by including the delay as one of the fitted model parameters. The smaller ROIs were then fittedwith the delay fixed to this value.
Fowler et al. (1995) have used graphical analysis for irreversible systems to calculate the net influxrate Ki. Ki were taken as an average of slopes between 6 and 45 min and 6 and 55 min [Fowler etal., 1995].
Estimation of K1 and k3 using “linear method”
Fowler et al. (1988, 1995) and Logan et al. (2000) estimated the three-compartment modelparameters using traditional nonlinear least squares approach.
Fowler et al. (1997, 1999) and Logan et al. (2000) estimated the three-compartment modelparameters K1 and k3 in a procedure which involves also graphical analysis:
1) Ki is calculated using the average of graphical analysis slopes between 6-45 min and 7-55
2) K1 (and k2+k3) are estimated with bilinear regression using a modification of the method of
Blomqvist (Eq. 1); note that equations in the original articles from years 1997 and 1998 donot contain the necessary square brackets. Logan et al. (2000) describe this process in moredetail: Several values for K1 were estimated by successively increasing the maximum time Tfrom 5 to 18 min, because K1 is more sensitive to data at earlier time points; an average K1was used in the next step.
k3 is calculated by solving it from the equation that relates Ki to the three-compartment
The estimates of K1 and k3 from this linear method correlated very well with the estimates fromthe nonlinear method [Logan et al., 2000]. No noise-induced bias was noticed in the linear method,and the repeatability was also similar.
K1 and blood flow
Extraction of [11C]L-deprenyl-D2 is high, and assuming that it is 1, then K1 would equal plasmaflow, that is about 40% of blood flow. Therefore, the K1 estimates by Logan et al. (2000), rangingfrom 0.476 to 0.845, are quite high.
The step 2) may lead to an overestimation of K1, if the blood volume in tissue is not considered:blood volume correction was not mentioned by Fowler et al. (1997, 1999) or Logan et al. (2000).
Graphical method (Gjedde-Patlak plot) can be used to estimate the net MAO B uptake using eithermetabolite corrected plasma or reference tissue with no MAO B as model input. To compensate thesignificant amount of MAO B in cerebellum, the cerebellar time-activity curves can be multipliedby a mono-exponential function to correct the deviation from linearity [Bergström et al., 1998].
However, cerebellar MAO B activity is probably not constant between individuals, although inclinical studies this methods has been used [Kumlien et al., 2001], and even less so in MAO Binhibition studies.
Note that the results of graphical method are not independent from blood flow, although the floweffects may be smaller than with SUV.
Bergström M, Kumlien E, Lilja A, Tyrefors N, Westerberg G, Lånström B. Temporal lobe epilepsy visualized with PETwith 11C-L-deuterium-deprenyl - analysis of kinetic data. Acta Neurol. Scand. 1998; 98: 224-231.
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Fowler JS, Logan J, Wang G-J, Volkow ND. Monoamine oxidase and cigarette smoking. Neurotoxicol. 2003; 24: 75-82.
Fowler JS, Logan J, Wang G-J, Volkow ND, Telang F, Ding Y-S, Shea C, Garza V, Xu Y, Li Z, Alexoff D, Vaska P,Ferrieri R, Schlyer D, Zhu W, Gatley SJ. Comparison of the binding of the irreversible monoamine oxidase tracers,[11C]clorgyline and [11C]l-deprenyl in brain and peripheral organs in humans. Nucl. Med. Biol. 2004; 31: 313-319.
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Fowler JS, Wolf AP, MacGregor RR, Dewey SL, Logan J, Schlyer DJ, Langstrom B. Mechanistic positron emissiontomography studies: demonstration of a deuterium isotope effect in the monoamine oxidase-catalyzed binding of[11C]L-deprenyl in living baboon brain. J. Neurochem. 1988; 51: 1524-1534.
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Lammertsma AA, Bench CJ, Price GW, Cremer JE, Luthra SK, Turton D, Wood ND, Frackowiak RSJ. Measurement ofCerebral Monoamine Oxidase B Activity Using L-[11C]Deprenyl and Dynamic Positron Emission Tomography. J.
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Logan J, Fowler JS, Volkow ND, Wang G-J, MacGregor RR, Shea C. Reproducibility of repeated measures ofdeuterium substituted [11C]L-deprenyl ([11C]L-deprenyl-D2) binding in the human brain. Nucl. Med. Biol. 2000; 27:43-49.
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