Image-Derived Input Functions for Quantification of A1 Adenosine Receptors Availability in Mice Brains Using PET and [18F]CPFPX.

Xuan He,Johannes Ermert,David Elmenhorst,Andreas Bauer,Simone Beer,Franziska Wedekind,Bernd Neumaier,Alexander Drzezga,Tina Kroll,Angela Oskamp

doi:10.3389/fphys.2019.01617

Abstract

PurposeIn vivo imaging for the A1 adenosine receptors (A1ARs) with positron emission tomography (PET) using 8-cyclopentyl-3-(3-[18F]fluoropropyl)-1-propylxan- thine ([18F]CPFPX) has become an important tool for studying physiological processes quantitatively in mice. However, the measurement of arterial input functions (AIFs) on mice is a method with restricted applicability because of the small total blood volume and the related difficulties in withdrawing blood. Therefore, the aim of this study was to extract an appropriate [18F]CPFPX image-derived input function (IDIF) from dynamic PET images of mice.ProceduresIn this study, five mice were scanned with [18F]CPFPX for 60 min. Arterial blood samples (n = 7 per animal) were collected from the femoral artery and corrected for metabolites. To generate IDIFs, three different approaches were selected: (A) volume of interest (VOI) placed over the heart (cube, 10 mm); (B) VOI set over abdominal vena cava/aorta region with a cuboid (5 × 5 × 15 mm); and (C) with 1 × 1 × 1 mm voxels on five consecutive slices. A calculated scaling factor (α) was used to correct for partial volume effect; the method of obtaining the total metabolite correction of [18F]CPFPX for IDIFs was developed. Three IDIFs were validated by comparison with AIF. Validation included the following: visual performance; computing area under the curve (AUC) ratios (IDIF/AIF) of whole-blood curves and parent curves; and the mean distribution volume (VT) ratios (IDIF/AIF) of A1ARs calculated by Logan plot and two-tissue compartment model.ResultsCompared with the AIF, the IDIF with VOI over heart showed the best performance among the three IDIFs after scaling by 1.77 (α) in terms of visual analysis, AUC ratios (IDIF/AIF; whole-blood AUC ratio, 1.03 ± 0.06; parent curve AUC ratio, 1.01 ± 0.10) and VT ratios (IDIF/AIF; Logan VT ratio, 1.00 ± 0.17; two-tissue compartment model VT ratio, 1.00 ± 0.13) evaluation. The A1ARs distribution of average parametric images was in good accordance to autoradiography of the mouse brain.ConclusionThe proposed study provides evidence that IDIF with VOI over heart can replace AIF effectively for quantification of A1ARs using PET and [18F]CPFPX in mice brains.

Highlights

The A1 adenosine receptors (A1ARs) are involved in various neurological as well as psychiatric disorders (Paul et al, 2011), and play significant role in processes such as sleep– wake regulation (Porkka-Heiskanen and Kalinchuk, 2011) and memory consolidation (Gessi et al, 2011; Paul et al, 2011)
Compared with the arterial input function (AIF), the image-derived input function (IDIF) with volume of interest (VOI) over heart showed the best performance among the three IDIFs after scaling by 1.77 (α) in terms of visual analysis, area under the curve (AUC) ratios (IDIF/AIF; whole-blood AUC ratio, 1.03 ± 0.06; parent curve AUC ratio, 1.01 ± 0.10) and VT ratios (IDIF/AIF; Logan VT ratio, 1.00 ± 0.17; two-tissue compartment model VT ratio, 1.00 ± 0.13) evaluation
The tails of whole-blood curves obtained by three different IDIF approaches generally matched closely with the reference arterial inputs

Summary

Introduction

The A1 adenosine receptors (A1ARs) are involved in various neurological as well as psychiatric disorders (Paul et al, 2011), and play significant role in processes such as sleep– wake regulation (Porkka-Heiskanen and Kalinchuk, 2011) and memory consolidation (Gessi et al, 2011; Paul et al, 2011). Small animal imaging could simplify the evaluation process of these compounds; various mice models of adenosine-related diseases might help to identify potential applications (Elmenhorst et al, 2013). PET with the radiotracer 8-cyclopentyl-3-(3-[18F]fluoropropyl)1-propylxanthine ([18F]CPFPX) can be used to quantify the in vivo concentration of A1ARs in the brain (Bauer et al, 2003). For this quantification, the concentration of parent radiotracer in plasma is necessary as the input function to the brain. The arterial input function (AIF) is still the gold standard (Meyer et al, 2006; Chen et al, 2007; Zanotti-Fregonara et al, 2009a) for quantification of target receptors via the invasive procedure of arterial cannulation. Multiple blood samplings in mice have often conducted as a terminal procedure preventing longitudinal studies within individual (Kim et al, 2006; Ferl et al, 2007; Wu et al, 2007)

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