Kinetics of the amino acid uptake tracer O-(2-[18F]fluoroethyl)-L-tyrosine (FET) in human brain

Abstract

Background: The large neutral amino acid [¹⁸F]fluoroethoxy-L-tyrosine ([¹⁸F]FET) is a popular tracer for detection and staging of intracranial tumors by positron emission tomography (PET). While its high tumoral uptake reflects over-expression of the L-type amino acid transporter (LAT1), there is little knowledge about the kinetics of [¹⁸F]FET uptake in healthy brain tissue, owing to the limited PET data in healthy volunteers, and to the requirement of an arterial input function for compartmental analysis. To address this, we used long axial field-of-view (LAFOV) dynamic 40-min recordings of 28 post-operative patients with intracranial tumors to undertake parametric brain mapping relative to an image-derived arterial input function (IDIF) obtained from the aorta. We averaged the individual parametric maps to obtain estimates of the physiological uptake relatively unaffected by individual residual lesions and resections, and tested simplified single-frame methods for quantitation.

Results: The analyses yielded estimates of regional unidirectional blood-brain clearance K₁ (0.00825-0.0244 ml g^-1 min^-1), net blood-brain clearance K_in (0.00448-0.00913 ml g^-1 min^-1), and equilibrium distribution volume V_T (0.126-0.495 ml g^-1), where the lowest values depict white matter, and the highest values cerebellum. In our test of a simplified quantitation of [¹⁸F]FET uptake from single frame recordings, i.e., Gjedde-Patlak multilinear graphic analyses of K₁ at five min post-injection and K_in at 40 min post injection, results were in good agreement with the analyses from the dynamic recordings (< 10% error).

Conclusions: Compartmental analysis results for [¹⁸F]FET uptake in extra-tumoral human brain regions are in accord with the few prior reports, mainly obtained in experimental animals, and support the use of single frame quantitation. Present findings in relatively healthy brain should inform the interpretation of pathological [¹⁸F]FET uptake in tumors.

Keywords: Blood brain barrier; Brain; L-type amino acid transporter; Large neutral amino acids; Physiological; Positron emission tomography (PET); [18F]Fluoroethoxy-L-tyrosine (FET).

Fig. 1

A Logarithmic transformation of the image-derived input function (IDIF) for [¹⁸F]FET in a representative individual decomposed into its three kinetic phases with fits of λ₁, λ₂, and λ₃. B Correlation of [¹⁸F]FET area under the curves (AUCs) for 0–5 and 0–40 min post-injection with the corresponding terminal arterial blood concentrations measured in the 4–5 and 35–40 min frames (AUC₅ = 8.0*C_a(T₅) + 19, r = 0.90; AUC₄₀ = 47*C_a(T₄₀) + 39, r = 0.92). C Multilinear graphic analysis (Gjedde-Patlak plot) of [¹⁸F]FET uptake in cerebellum during the first 2.5 min, i.e., unidirectional blood–brain clearance (K₁; ml g⁻¹ min⁻¹) and during the interval 10–25 min, i.e. net blood–brain clearance (K_in; ml g⁻¹ min⁻¹), where Θ is the normalized arterial input, i.e., $\mathrm{\Theta }={\int }_0^t{C}_{a}dt/C_a$. D Representative fittings of one-tissue compartment model (1TCM) in PMOD to time-activity curves measured in white matter ( ×), putamen (Δ), and cerebellum grey matter ( +). E Multilinear graphic analysis (Gjedde-Patlak plot) of K_in (ml g⁻¹ min⁻¹) in PMOD in the same three brain regions. F Arterial input Logan plots of the equilibrium distribution volume (linear fits: V_T; ml g⁻¹) in the same three brain regions

Fig. 2

Mean parametric maps for [¹⁸F]FET unidirectional blood brain clearance (K₁; ml g⁻¹ min⁻¹), the fractional rate constant for washout from brain (k₂; min⁻¹), and their ratio, the distribution volume (V_T, ml g⁻¹), calculated by a reversible one tissue compartment model (1TCM) relative to the image derived input function. Maps represent the mean from (n = 28) patients

Fig. 3

Mean parametric maps to Gjedde-Patlak (multi)-linear graphic analysis (LGA) of the [¹⁸F]FET unidirectional blood–brain clearance (K₁; ml g⁻¹ min⁻¹) during the first 5 min of the dynamic PET recordings, and net blood brain clearance (K_in; ml g⁻¹ min⁻¹) to late phase 10–40 min LGA, along with Logan distribution volume (V_T; ml g⁻¹) analysis of the 40 min recordings. Maps represent the mean from (n = 28) patients, all calculated relative to their respective image derived input functions