Publikationsrepositorium - Helmholtz-Zentrum Dresden-Rossendorf

Aim:

Nicotinic α4β2* acetylcholine receptors (nAChR) are an important target for diagnostic neuroimaging because of their involvement in Alzheimer's disease, Parkinson's disease, tobacco and alcohol addiction. 2-[¹⁸F]FA-85380 (2-FA) has been used extensively for PET imaging of α4β2* receptors but is limited as biomarker by its unfavourable slow kinetic. The newly developed radiotracer (-)-[¹⁸F]-Flubatine (Flubatine) shows a significantly improved brain uptake, receptor affinity and selectivity (1). Here we estimated the compartmental parameters of both tracers by full kinetic modeling and compared them.

Materials and methods:

After intravenous administration of ~370 MBq radiotracer PET brain imaging was performed in 20 healthy controls with Flubatine (age 70.6±4.6, scan duration 90 min) and in 7 healthy controls with 2-FA (age 60.7±9.0, scan duration 420 min) using an ECAT EXACT HR+ system. PET frames were motion corrected with SPM2 and kinetic modeling using a 1-tissue compartment model (1TCM) with arterial input-function was applied to the volume of interest (VOI) based tissue time-activity curves (TACs) generated for 29 brain regions (anatomically defined via MRI co-registration). The model-based receptor parameter used was the total distribution volume V_T (ml/cm³), tracer uptake was measured by K₁ (ml/cm³/min) and tracer tissue clearance by k₂ (1/min).

Results:

For both tracers TACs of all 29 brain regions could be described appropriately with the 1TCM and all kinetic parameters could be reliably estimated from the PET data. Regional V_T increased as expected with regional nAChR density. Parameters of Flubatine in characteristic regions with very low, medium and high receptor density were: Corpus callosum (K₁= 0.18±0.04, k₂= 0.032±0.004, V_T= 5.68±1.01), Frontal cortex (K₁= 0.37±0.04, k₂= 0.040±0.003, V_T= 9.18±0.59), Thalamus (K₁= 0.48±0.06, k₂= 0.020±0.003, V_T= 25.03±3.33). The respective parameters of 2-FA were: Corpus callosum (K₁= 0.063±0.009, k₂= 0.014±0.003, V_T= 4.45±0.65), Frontal cortex (K₁= 0.099±0.013, k₂= 0.018±0.001, V_T= 5.42±0.56), Thalamus (K₁= 0.13±0.019, k₂= 0.010±0.001, V_T= 13.06±2.62).

Conclusions:

Flubatine is superior to 2-FA in tracer uptake velocity (characterized by K₁), velocity of washout (characterized by k₂) and in the amount of measured specific binding (characterized by V_T-target - V_T-reference). It shows a threefold higher uptake rate constant K₁ and a twofold higher washout rate constant k₂, providing the rational for much shorter scan durations in case of Flubatine. These results are in good agreement with our former findings in an animal (pig) model (1).

Reference:

1. P. Brust, ..O. Sabri: In vivo measurement of nicotinic acetylcholine receptors with [¹⁸F]Norchloro-Fluoro-Homoepibatidine (Flubatine). Synapse 2008;62:205-218.