Kinetic Modeling of N-[¹¹C]Methylpiperidin-4-yl Propionate: Alternatives for Analysis of an Irreversible Positron Emission Tomography Tracer for Measurement of Acetylcholinesterase Activity in Human Brain

Abstract

Summary: N-[IIC]Methylpiperidin-4-yl propionate(C I ClPMP) is a substrate for hydrolysis by acetylcholinester ase (AChE) . This work evaluates kinetic analysis alternatives for estimation of relative AChE activity using dynamic positron emission tomography (PET) studies of rIIC]PMP. The PET studies were performed on three groups of subjects: (I) 12 normal volunteer subjects, aged 20 to 45 years, who received a single intravenbus injection of 16 to 32 mCi of C I ClPMP; (2) six subjects, aged 21 to 44 years, who received two 16-mCi injections of C IC]PMP (baseline and visual stimulation, re spectively); and (3) five subjects, aged 24 to 40 years, who received two 16-mCi injections separated by 200 minutes (baseline and after a I-hour constant infusion of 1.5 mg of physostigmine, respectively) . Dynamic acquisition consisted of a 17-frame sequence over 80 minutes. All analysis methods were based on a first-order kinetic model consisting of two tissue compartments with the parameter k3' representing PMP hydrolysis, being the index of AChE activity. Four different schemes were used to estimate k3: (1) an unconstrained non linear least-squares fit estimating blood-brain barrier transport Positron emission tomography (PET) offers the ability to quantify biochemical features in living humans through the use of radiolabeled tracers and the applica tion of tracer kinetics and compartmental analysis. This study evaluates kinetic analysis alternatives for charac- 1150parameters, K I and k2' in addition to the hydrolysis rate con stant k3; (2) and (3) , two methods of constraining the fit by fixing the volume of distribution of free tracer (DVfree); and (4), a direct estimation of k3 without use of an arterial input function based on the shape of the tissue time-activity curve alone. Results showed that k3 values from the unconstrained fitting and no input methods were estimated with similar ac curacy, whereas the two methods using DVfrce constraints yielded similar results. The authors conclude that the optimal analysis method for C iClPMP differs as a function of AChE activity. All four methods gave precise measures of k3 in re gions with low AChE activity (-10% coefficient of variation in cortex), but surprisingly, with unconstrained methods yielding estimates with lower variability than constrained methods. In regions with moderate to high AChE activity, constrained methods were required to yield meaningful estimates and were superior to the unconstrained methods. Key Words:N-C I Clmethylpiperidin-4-yl propionate-Tracer kinetics Acetylcholinesterase-Positron emission tomography.terizing the in vivo behavior of N-e l C]methylpiperidin-4-yl propionate (C l C]PMP) to yield quantitative esti mates of the model parameter k3 as an index of regional acetylcholinesterase (AChE) activity in the human brain. Acetylcholine, the acetic acid ester of choline, is a neu rotransmitter present in cholinergic synapses of the CNS. Acetylcholinesterase is an enzyme of the CNS (as well as muscles and red cells) that catalyzes the hydrolysis...

Estimation of Plasma IC50 of Donepezil Hydrochloride for Brain Acetylcholinesterase Inhibition in Monkey Using N-[11C]methylpiperidin-4-yl Acetate ([11C]MP4A) and PET

“…In recent years, N-[ 11 C]methylpiperidin-4-yl acetate ([ 11 C]MP4A) (Irie et al, 1994) and N-[ 11 C]methylpiperidin-4-yl propionate ([ 11 C]MP4P) (Irie et al, 1994;Kilbourn et al, 1996) have been developed as radiotracers for brain AChE mapping and applied to quantification of neocortical AChE activity in healthy subjects (Namba et al, 1999;Koeppe et al, 1999) and in patients with AD (Iyo et al, 1997;Kuhl et al, 1999). Both tracers were also applied to evaluating the inhibitory effect of donepezil on brain AChE activity in AD patients (Kuhl et al, 2000;Shinotoh et al, 2001;Kaasinen et al, 2002) and in monkeys (Tsukada et al, 2004).…”

Strategies for Quantifying Pet Imaging Data from Tracer Studies of Brain Receptors and Enzymes

“…Different approaches to optimizing k3 are illustratedin Koeppe et al (1999) for the ligand [1lC]PMP which binds irreversiblyto acetylcholinesterase. These included unconstrained estimation of all threeparametersand constrained estimation of ks by fixing the K1/k2 ratio.…”

“…This method was applied to estimation of acteylcholinesterase activity and was found to be suitable for regions of low enzyme activity (Koeppe et al 1999). Patlak and Blasberg (1985) extended the graphical analysis for irreversible ligands to an analysis using a reference region in place of the plasma input.…”

“…When K1 -Ki, only one parametercan be determined, KI, and no information can be obtained about enzyme/receptor concentration.). In the regions of higher specific binding the estimates of k3 become much more variable, althoughthey are highly correlated to k2 (Logan et al 2000a;Koeppe et al 1999). In order to reduce this variability, Fowler et al (1995) have used the parameterAk3 which is much more stable since it contains the ratio k3/k2.…”

“…Some of the tracersused and the receptorshransportersthatthey label are: [1lC]raclopride (Farde et al 1989;Volkow et al 1993;Hietala et al 1999), [1*C]N-methylspiperone (Wong et al 1986a(Wong et al ,1986b, [1231] epidepride for the D2 dopamine receptor; [1lC]-Schering 23390 (Farde et al 1987;Suharaet al 1991), [1*C]NNC 112 (Abi-Dargham et al 2000), for the D1 receptor; [1lC]benztropine (Dewey et al 1993a), scopolamine (Frey et al 1992), [llC] tropanyl benzilate (Koeppe et al 1994), [llC] NMPB (Zubieta et al 1998), [lgF]FP-TZTP, for the muscarinic cholinergic system; [1lC] cocaine (l?owler et al 1989) [1lC]d-threo methlyphenidate Ding et al 1994Ding et al , 1997, for the dopamine transporter;[1lC]dihydrotetrabenazine (Koeppe et al 1995), for the vesicular monoamine transporter;[1lC]carfentanil (Frost et al 1989) for the opiate receptor; [11C]WAY-100635 (Mathis et al1994;Farde et al1998), for the 5HT1A; [llC]flurnazenil (price et al 1993) and [12311 iomazenil (Bremner et al 2000) for the benzodiazepine receptor. Examples of ligands used for the study of brain enzymes are [llC]Ldeprenyl and [*lC]L-deprenyl-D2 (MAO B) (Fowler et al 1987, [llC]clorgyline (MAO A) (Fowler et al 1987), and [llC] PMP (acetylcholinesterase) (Koeppe et al 1999). …”