Date Published: May 31, 2019
Publisher: Public Library of Science
Author(s): Mark G. MacAskill, Tashfeen Walton, Lewis Williams, Timaeus E. F. Morgan, Carlos José Alcaide-Corral, Marc R. Dweck, Gillian A. Gray, David E. Newby, Christophe Lucatelli, Andrew Sutherland, Sally L. Pimlott, Adriana A. S. Tavares, Pradeep K. Garg.
Positron Emission Tomography (PET) imaging with selective 18 kDa translocator protein (TSPO) radiotracers has contributed to our understanding on the role of inflammation in disease development and progression. With an increasing number of rodent models of human disease and expansion of the preclinical PET imaging base worldwide, accurate quantification of longitudinal rodent TSPO PET datasets is necessary. This is particularly relevant as TSPO PET quantification relies on invasive blood sampling due to lack of a suitable tissue reference region. Here we investigate the kinetics and quantification bias of a novel TSPO radiotracer [18F]AB5186 in rats using automatic, manual and image derived input functions.
[18F]AB5186 was administered intravenously and dynamic PET imaging was acquired over 2 hours. Arterial blood was collected manually to derive a population based input function or using an automatic blood sampler to derive a plasma input function. Manually sampled blood was also used to analyze the [18F]AB5186 radiometabolite profile in plasma and applied to all groups as a population based dataset. Kinetic models were used to estimate distribution volumes (VT) and [18F]AB5186 outcome measure bias was determined.
[18F]AB5186 distribution in rats was consistent with TSPO expression and at 2 h post-injection 50% of parent compound was still present in plasma. Population based manual sampling methods and image derived input function (IDIF) underestimated VT by ~50% and 88% compared with automatic blood sampling, respectively. The VT variability was lower when using IDIF versus arterial blood sampling methods and analysis of the Bland-Altman plots showed a good agreement between methods of analysis.
Quantification of TSPO PET rodent data using image-derived methods, which are more amenable for longitudinal scanning of small animals, yields outcome measures with reduced variability and good agreement, albeit biased, compared with invasive blood sampling methods.
The 18 kDa translocator protein (TSPO), previously known as the peripheral benzodiazepine receptor, is a five-membrane domain protein expressed in the outer membrane of the mitochondria of different cell types present in peripheral tissues and the central nervous system (CNS). In the periphery, high TSPO levels are reported in immune cells, including macrophages [1–3]. In the CNS, high levels of TSPO are associated with activated microglia and astrocytes [4–8]. At the organ level, the highest expression of TSPO is reported in the lungs and in the heart, and low levels are present in the healthy brain [9,10].
PET studies in rats showed that, following intravenous (i.v.) bolus injection, [18F]AB5186 rapidly entered the brain with peak SUV in whole brain of 0.83±0.05 g/mL (mean±SD, n = 3) and displayed a distribution consistent with known TSPO expression, being highest in the heart and lungs (5.92±0.24 g/mL and 4.87±1.93 g/mL, respectively, mean±SD, n = 3) and lowest in the brain (Fig 2). The radiotracer uptake profile was consistent with reversible binding kinetics. Regional TACs in whole organs and brain regions following i.v. bolus of [18F]AB5186 are shown in Fig 2C and 2D, respectively.
This study investigated the quantification bias of kinetic modelling outcome measures of rodent TSPO PET when using image derived input function versus two invasive blood sampling methods. To our knowledge, this is the first study to date investigating such quantification bias of a TSPO PET radiotracer in rodents. Results collected here showed that [18F]AB5186 has a consistent distribution with TSPO expression [9,10] and comparable outcome measures to other previously developed radiotracers. For example, injection of [11C]PK11195 into naïve Sprague-Dawley rats yielded a VT in brain of 3.2 mL/cm3 , versus our [18F]AB5186 estimated VT in brain of 3.3 mL/cm3 using the automatic blood sampling invasive quantification methods. Metabolism of [18F]AB5186 in rat blood was slower than other previously developed TSPO radiotracers in rats, namely [18F]DPA-714 , [18F]GE180  and [11C]DPA-713 .
Quantification of TSPO PET rat data using [18F]AB5186 can be achieved using image derived input function methods with a VOI placed inside the left ventricle. Despite bias relative to invasive methods of quantification, outcome measures obtained using image derived input functions are robust, strongly agree with outcome measures from invasive methods, are less variable and potentially more amenable for longitudinal scanning of small animals. These results may encourage others to undertake kinetic modelling of rodent PET data due to the suitability and feasibility of image derived input functions.