Novel Approach to Repeated Arterial Blood Sampling in Small Animal PET: Application in a Test-Retest Study with the Adenosine A1 Receptor Ligand [11C]MPDX
Novel Approach to Repeated Arterial Blood Sampling in Small Animal PET: Application in a Test-Retest Study with the Adenosine A1 11 Receptor Ligand [ C]MPDX
Jürgen
W. A. Sijbesma 2
Xiaoyun Zhou 2
David Vállez García 2
Martin C. Houwertjes 1
Janine Doorduin 2
Chantal Kwizera 2
Peter Meerlo 0
Rudi A. Dierckx 2
Riemer H. J. A. Slart 2 3
Philip H. Elsinga 2
Aren van
Waarde 2
0 Groningen Institute for Evolutionary Life Sciences, University of Groningen , Nijenborgh 7, 9747AG, Groningen , The Netherlands
1 Experimental Anesthesiology and Clinical Pharmacology Research Group, University of Groningen , Antonius Deusinglaan 1, 9713 AV, Groningen , The Netherlands
2 University Medical Center Groningen, Department of Nuclear Medicine and Molecular Imaging, University of Groningen , Hanzeplein 1, 9713 GZ, Groningen , The Netherlands
3 Department of Biomedical Photonic Imaging, University of Twente , P.O. Box 217, 7500AE, Enschede , The Netherlands
Purpose: Small animal positron emission tomography (PET) can be used to detect small changes in neuroreceptor availability. This often requires rapid arterial blood sampling. However, current catheterization procedures do not allow repeated blood sampling. We have developed a procedure which allows arterial sampling on repeated occasions in the same animal. Procedures: Eleven male Wistar rats were two times catheterized via a superficial branch of a femoral artery and scanned with [11C]MPDX and blood sampling. PET images were coregistered to a magnetic resonance imaging (MRI) template. Regional tracer distribution volumes (VT) in the brain were calculated by the Logan analysis. The procedure was repeated after 1 week. Results: Surgery was successful in 90 % of the cases, and discomfort was minor. The VT data showed small differences between test and retest, low between subject variability, and a strong agreement between and within subjects. Conclusion: Repeated quantitative imaging with a high reproducibility is possible with this approach.
Test-retest reproducibility; Positron emission tomography; Adenosine A1 receptor; Brain; Arterial blood sampling
Introduction
Small animal positron emission tomography (PET) is a
wellestablished method to visualize neuroreceptors, protein
aggregates, ion channels, enzymes, or transporter proteins
in the brain and other organs, using radiolabeled
compounds. In many cases, blood sampling is required to
determine the dynamics of radiotracer clearance and
metabolism for quantification of specific binding in the tissue of
interest, especially when a reference tissue as input for a
reference tissue model (RTM) is not available [
1–3
].
Catheterization of an artery is needed for rapid collection
of arterial plasma during the scan. Plasma samples are used
to measure radioactivity and to determine the ratio of intact
parent tracer and radioactive metabolites in these samples to
acquire an input function for the analysis. For arterial plasma
collection, the femoral arteries are often used [
4–6
]. The
arteries are easy accessible, required materials for the
catheterization are cheap, and the impaired blood flow does
not affect major organs like the brain or abdomen, but
because of the invasiveness of this technique, rats must be
euthanized after the scan [
4–6
]. This makes longitudinal
studies with multiple scans in the same animal impossible.
For this reason, we have developed a cheap and
technically easy surgical procedure which has the same
benefits as the commonly used catheterization of a femoral
artery but is minimally invasive and allows repeated
catheterization and blood collection. Here, we describe this
procedure and use the adenosine A1 receptor ligand
[11C]MPDX to validate it. In order to assess variability and
repeatability of the PET scans, we performed a test-retest
study in which 11 rats were subjected to the novel surgical
procedure, and two PET scans with the adenosine A1
receptor ligand and rapid arterial blood sampling were made
in each animal, with an interval of 1 week. We show that
repeated quantitative PET scans of neuroreceptors can be
made in the same rat, even when rapid arterial blood
sampling is required.
Materials and Methods
Animals
Male Wistar Unilever rats (8 ± 2 weeks of age) were obtained from
Harlan (Boxmeer, the Netherlands). After delivery, the animals
were acclimated for at least 7 days to recover from the transport and
adapt to the new housing conditions. The rats were housed in
Makrolon cages at a constant temperature of 21 ± 2 °C, maintained
at a 12-h light/12-h dark regime, and fed standard chow ad libitum.
The experimental protocol was approved by the Institutional
Animal Care and Use Committee of Groningen University (File
No. 5841D). All experiments were performed by licensed
investigators in compliance with the Law on Animal Experiments of
The Netherlands.
Surgery and Blood Collection
Thirty minutes before the start of each PET scan, each rat was
anesthetized using a mixture of isoflu (...truncated)