Evaluation of [11C]CS1P1 in Healthy Young and Older Adults

Abstract

Background and purpose: Sphingosine-1-phosphate receptor 1 (S1PR1) is a key regulator of neuroinflammation and plays a crucial role in multiple neurodegenerative diseases. [¹¹C]CS1P1 is a novel PET tracer for measuring expression levels of S1PR1 in humans. Before widespread application, its quantification must be established and evaluated in healthy young and old adults through characterization of binding topographies, kinetics, and tracer metabolism rates.

Materials and methods: We acquired dynamic [¹¹C]CS1P1 emission data from 29 healthy controls and investigated the topography of [¹¹C]CS1P1 uptake, radio-labeled metabolites of the tracer, an image-derived input function estimation, and tissue compartment modeling.

Results: The image-derived input function approximated the arterially sampled input function. Further, radio-labeled metabolites of the tracer accumulated linearly throughout the scan and demonstrated consistency across participants. A 2-tissue compartment model fitted the observed emission data well, consistent with previously reported nonhuman primate studies. Kinetic modeling using the image-derived input functions, corrected by population estimates of tracer metabolism, provided a good fit for tissue activity curves. Graphical Logan analysis reliably estimated volume of distribution (Vt), and Vt closely reproduced S1PR1 distribution in the brain.

Conclusions: In this study, we have established a quantitative ¹¹C]CS1P1 PET processing approach by using a 2-tissue compartment model and imaging-derived input function with population metabolite correction. [¹¹C]CS1P1 PET reflects S1PR1 topography and supports its use for investigating neuroinflammation in humans.

FIGURE 1.

Mean SUV [11C]CS1P1 images derived from 60–75 minutes post injection. Highest signal is observed in subcortical grey structures (top and right white arrows), followed by cortex, and lowest signal is observed in the white matter. Extracranial uptake was high in the salivary glands (bottom white arrow).

FIGURE 2.

A) Comparison of activity measures using image-derived and arterial blood sampling methods during the first five minutes (left) after radiotracer injection and during the remainder of the scan (right). B) Comparison of area under the curve for the two input function estimation methods.

FIGURE 3.

Individual and group tracer parent fractions as measured by HPLC during the first 60 minutes of PET acquisition. No difference was observed between young and older groups (group means in bold lines).

FIGURE 4.

A) Time activity curves for ROIs, including the image derived input function (IDIF), cerebral cortex, normal appearing white matter (NAWM), Subcortical grey structures, cerebrospinal fluid (CSF), and choroid plexus. The main panel highlights the initial influx of tracer, with the heights of the initial peak activity in descending order being IDIF, choroid plexus, cortex, subcortical grey structures, NAWM, and CSF. The inset shows the remainder of the scan, with the final values being highest in the cortex, subcortical grey, and NAWM, followed by choroid plexus, IDIF, and CSF. B) Measured regional values for an example region (cortex) and the fitted values from a two-tissue compartment model. The lower graph shows the difference between measured and estimated values. C) Comparison of Akaike Information Criterion (AIC) values for two-tissue compartment models featuring reversible and irreversible binding. D) Comparison of AIC values for two-tissue compartment and one-tissue compartment models.

FIGURE 5.

A) Scatter plot (left) and Bland-Altman plot (right) comparing Vt estimates for cortex and NAWM using arterial blood sampling and calibrated IDIF. B) Scatter (left) and Bland-Altman (right) plots comparing Vt estimates for cortex and NAWM using individual and population tracer metabolism rates. C) Scatter plots showing similar cortex to NAWM Vt ratios when substituting IDIF for AIF (left) and population for individual tracer metabolism rates (right).

FIGURE 6.

A) Comparison of Vt estimates between young and older participants for the Cortex, NAWM, and Subcortical gray structures. The difference between young and old groups was not significant for any region. B) Comparison of Vt estimates from initial and follow-up scans (n=6) for the same regions. Model fitting failed for NAWM for one scan (point not shown).

FIGURE 7.

A) Example of a Logan plot for a typical cortex ROI, showing best fit line for the last 8 frames of the scan with a Vt estimate (slope) of approximately 6.4. B) Comparison of Vt estimates between two-tissue compartment models and Logan plot analysis. C) Bland Altman plot showing differences between the two methods.