MP4A (Nagatsuka RLS Ref): Multi-linear Reference Tissue Model for [11C]-MP4A (RLS)

The MP4A (Nagatsuka RLS Ref) model has been developed for the non-invasive quantification method (RLS) of the acetylcholinesterase (AChE) activity in the human brain from measurements with the ¹¹C-MP4A acetylcholine analog [1]. In contrast to reference methods for receptor tracers which use a reference devoid of specific binding, the present method uses a reference with very high AChE activity which immediately traps the tracer so there is no washout. C_T(t) is the TAC from a cortical target region, and C_T'(t) the TAC from the reference region (striatum or cerebellum). k₃ represents the rate of tracer hydrolysis by AChE.

By applying the method of Blomqvist, the following multi-linear equation is derived

PKIN Eq Nagatsuka RLS

It can be fitted to C_T(t) using multi-linear regression, yielding three regression coefficients from which three parameters of interest can be calculated:

Acquisition and Data Requirements

Image Data	A dynamic PET data set with [11C]-MP4A.
TAC 1	TAC from a cortical target region.
TAC 2	A suitable reference region must be selected as TAC 2. The findings in different publications indicate that cerebellum yields more stable results than striatum, most likely due to the higher impact of motion on the signal from the small striatum than the large cerebellum.

Model Preprocessing

Two regional TACs (TAC1 and TAC2) are needed for Model Preprocessing.

PXMOD MP4A Ref Model Pre-Processing

Threshold	Discrimination threshold for background masking.
R1	The delivery in the target region relative to the reference.
k2	The rate of washout from brain to blood.
k3	The main parameter, the rate of tracer hydrolysis by AChE.

Model Configuration

PXMOD MP4A Parameters

k3	The main parameter, the rate of tracer hydrolysis by AChE.
k2	The rate of washout from brain to blood.
R1	First coefficient of multilinear regression (Nagatsuka Eq. 3), representing the relative delivery K₁/K₁'.
P2	Second coefficient of multilinear regression (Nagatsuka Eq. 3), representing Rl*k₃
P3	Third coefficient of multilinear regression (Nagatsuka Eq. 3), representing -(k₂+k₃)

Reference

1. Nagatsuka Si S, Fukushi K, Shinotoh H, Namba H, Iyo M, Tanaka N, Aotsuka A, Ota T, Tanada S, Irie T: Kinetic analysis of [(11)C]MP4A using a high-radioactivity brain region that represents an integrated input function for measurement of cerebral acetylcholinesterase activity without arterial blood sampling. J Cereb Blood Flow Metab 2001, 21(11):1354-1366. DOI