Nuclear imaging of neuroinflammation: a comprehensive review of [11C]PK11195 challengers

Neurodegenerative, inflammatory and neoplastic brain disorders involve neuroinflammatory reactions, and a biomarker of neuroinflammation would be useful for diagnostic, drug development and therapy control of these frequent diseases. In vivo imaging can document the expression of the peripheral benzodiazepine receptor (PBR)/translocator protein 18 kDa (TSPO) that is linked to microglial activation and considered a hallmark of neuroinflammation. The prototype positron emission tomography tracer for PBR, [¹¹C]PK11195, has shown limitations that until now have slowed the clinical applications of PBR imaging. In recent years, dozens of new PET and SPECT radioligands for the PBR have been radiolabelled, and several have been evaluated in imaging protocols. Here we review the new PBR ligands proposed as challengers of [¹¹C]PK11195, critically analyze preclinical imaging studies and discuss their potential as neuroinflammation imaging agents.     

The translocator protein ligand [18F]DPA-714 images glioma and activated microglia in vivo

Purpose

In recent years there has been an increase in the development of radioligands targeting the 18-kDa translocator protein (TSPO). TSPO expression is well documented in activated microglia and serves as a biomarker for imaging neuroinflammation. In addition, TSPO has also been reported to be overexpressed in a number of cancer cell lines and human tumours including glioma. Here we investigated the use of [¹⁸F]DPA-714, a new TSPO positron emission tomography (PET) radioligand to image glioma in vivo.

Methods

We studied the uptake of [¹⁸F]DPA-714 in three different rat strains implanted with 9L rat glioma cells: Fischer (F), Wistar (W) and Sprague Dawley (SD) rats. Dynamic [¹⁸F]DPA-714 PET imaging, kinetic modelling of PET data and in vivo displacement studies using unlabelled DPA-714 and PK11195 were performed. Validation of TSPO expression in 9L glioma cell lines and intracranial 9L gliomas were investigated using Western blotting and immunohistochemistry of brain tissue sections.

Results

All rats showed significant [¹⁸F]DPA-714 PET accumulation at the site of 9L tumour implantation compared to the contralateral brain hemisphere with a difference in uptake among the three strains (F?>?W?>?SD). The radiotracer showed high specificity for TSPO as demonstrated by the significant reduction of [¹⁸F]DPA-714 binding in the tumour after administration of unlabelled DPA-714 or PK11195. TSPO expression was confirmed by Western blotting in 9L cells in vitro and by immunohistochemistry ex vivo.

Conclusion

The TSPO radioligand [¹⁸F]DPA-714 can be used for PET imaging of intracranial 9L glioma in different rat strains. This preclinical study demonstrates the feasibility of employing [¹⁸F]DPA-714 as an alternative radiotracer to image human glioma.     

[11C]-(R)PK11195 tracer kinetics in the brain of glioma patients and a comparison of two referencing approaches

Purpose

Translocator protein (TSPO) is a biomarker of neuroinflammation that can be imaged by PET using [¹¹C]-(R)PK11195. We sought to characterize the [¹¹C]-(R)PK11195 kinetics in gliomas of different histotypes and grades, and to compare two reference tissue input functions (supervised cluster analysis versus cerebellar grey matter) for the estimation of [¹¹C]-(R)PK11195 binding in gliomas and surrounding brain structures.

Methods

Twenty-three glioma patients and ten age-matched controls underwent structural MRI and dynamic [¹¹C]-(R)PK11195 PET scans. Tissue time–activity curves (TACs) were extracted from tumour regions as well as grey matter (GM) and white matter (WM) of the brains. Parametric maps of binding potential (BP_ND) were generated with the simplified reference tissue model using the two input functions, and were compared with each other. TSPO expression was assessed in tumour tissue sections by immunohistochemistry.

Results

Three types of regional kinetics were observed in individual tumour TACs: GM-like kinetics (n?=?6, clearance of the tracer similar to that in cerebellar GM), WM-like kinetics (n?=?8, clearance of the tracer similar to that in cerebral WM) and a form of mixed kinetics (n?=?9, intermediate rate of clearance). Such kinetic patterns differed between low-grade astrocytomas (WM-like kinetics) and oligodendrogliomas (GM-like and mixed kinetics), but were independent of tumour grade. There was good agreement between parametric maps of BP_ND derived from the two input functions in all controls and 10 of 23 glioma patients. In 13 of the 23 patients, BP_ND values derived from the supervised cluster input were systematically smaller than those using the cerebellar input. Immunohistochemistry confirmed that TSPO expression increased with tumour grade.

Conclusion

The three types of [¹¹C]-(R)PK11195 kinetics in gliomas are determined in part by tracer delivery, and indicated that kinetic analysis is a valuable tool in the study of gliomas with the potential for in vivo discrimination between low-grade astrocytomas and oligodendrogliomas. Supervised cluster and cerebellar input functions produced consistent BP_ND estimates in approximately half of the gliomas investigated, but had a systematic difference in the remainder. The cerebellar input is preferred based on theoretical and practical considerations.     

In vivo imaging of neuroinflammation in the rodent brain with [11C]SSR180575, a novel indoleacetamide radioligand of the translocator protein (18?kDa)

Purpose

Neuroinflammation is involved in neurological disorders through the activation of microglial cells. Imaging of neuroinflammation with radioligands for the translocator protein (18 kDa) (TSPO) could prove to be an attractive biomarker for disease diagnosis and therapeutic evaluation. The indoleacetamide-derived 7-chloro-N,N,5-trimethyl-4-oxo-3-phenyl-3,5-dihydro-4H-pyridazino[4,5-b]indole-1-acetamide, SSR180575, is a selective high-affinity TSPO ligand in human and rodents with neuroprotective effects.

Methods

Here we report the radiolabelling of SSR180575 with ¹¹C and in vitro and in vivo imaging in an acute model of neuroinflammation in rats.

Results

The image contrast and the binding of [¹¹C]SSR180575 are higher than that obtained with the isoquinoline-based TSPO radioligand, [¹¹C]PK11195. Competition studies demonstrate that [¹¹C]SSR180575 has high specific binding for the TSPO.

Conclusion

[¹¹C]SSR180575 is the first PET radioligand for the TSPO based on an indoleacetamide scaffold designed for imaging neuroinflammation in animal models and in the clinic.     

Preclinical in vivo and in vitro comparison of the translocator protein PET ligands [<Superscript>18</Superscript>F]PBR102 and [<Superscript>18</Superscript>F]PBR111

Purpose

To determine the metabolic profiles of the translocator protein ligands PBR102 and PBR111 in rat and human microsomes and compare their in vivo binding and metabolite uptake in the brain of non-human primates (Papio hamadryas) using PET-CT.

Methods

In vitro metabolic profiles of PBR102 and PBR111 in rat and human liver microsomes were assessed by liquid chromatography–tandem mass spectrometry. [¹⁸F]PBR102 and [¹⁸F]PBR111 were prepared by nucleophilic substitution of their corresponding p-toluenesulfonyl precursors with [¹⁸F]fluoride. List mode PET-CT brain imaging with arterial blood sampling was performed in non-human primates. Blood plasma measurements and metabolite analysis, using solid-phase extraction, provided the metabolite profile and metabolite-corrected input functions for kinetic model fitting. Blocking and displacement PET-CT scans, using PK11195, were performed.

Results

Microsomal analyses identified the O-de-alkylated, hydroxylated and N-de-ethyl derivatives of PBR102 and PBR111 as the main metabolites. The O-de-alkylated compounds were the major metabolites in both species; human liver microsomes were less active than those from rat. Metabolic profiles in vivo in non-human primates and previously published rat experiments were consistent with the microsomal results. PET-CT studies showed that K₁ was similar for baseline and blocking studies for both radiotracers; V_T was reduced during the blocking study, suggesting low non-specific binding and lack of appreciable metabolite uptake in the brain.

Conclusions

[¹⁸F]PBR102 and [¹⁸F]PBR111 have distinct metabolic profiles in rat and non-human primates. Radiometabolites contributed to non-specific binding and confounded in vivo brain analysis of [¹⁸F]PBR102 in rodents; the impact in primates was less pronounced. Both [¹⁸F]PBR102 and [¹⁸F]PBR111 are suitable for PET imaging of TSPO in vivo. In vitro metabolite studies can be used to predict in vivo radioligand metabolism and can assist in the design and development of better radioligands.

     

PET imaging of neuroinflammation in a rat traumatic brain injury model with radiolabeled TSPO ligand DPA-714

Purpose

The inflammatory response in injured brain parenchyma after traumatic brain injury (TBI) is crucial in the pathological process. In order to follow microglia activation and neuroinflammation after TBI, we performed PET imaging in a rat model of TBI using ¹⁸F-labeled DPA-714, a ligand of the 18-kDa translocator protein (TSPO).

Methods

TBI was induced in male SD rats by a controlled cortical impact. The success of the TBI model was confirmed by MRI. [¹⁸F]DPA-714 was synthesized using a slightly modified TRACERLab FX-FN module and an automated procedure. In vivo PET imaging was performed at different time points after surgery using an Inveon small-animal PET scanner. The specificity of [¹⁸F]DPA-714 was confirmed by a displacement study with an unlabeled competitive TSPO ligand, PK11195. Ex vivo autoradiography as well as immunofluorescence staining was carried out to confirm the in vivo PET results.

Results

Both in vivo T₂-weighted MR images and ex vivo TTC staining results revealed successful establishment of the TBI model. Compared with the sham-treated group, [¹⁸F]DPA-714 uptake was significantly higher in the injured brain area on PET images. Increased lesion-to-normal ratios of [¹⁸F]DPA-714 were observed in the brain of TBI rats on day 2 after surgery. Ratios peaked around day 6 (2.65?±?0.36) and then decreased gradually to nearly normal levels on day 28. The displacement study using PK11195 confirmed the specific binding of [¹⁸F]DPA-714 to TSPO. The results of ex vivo autoradiography were consistent with in vivo PET results. Immunofluorescence staining showed the time course of TSPO expression after TBI and the temporal and the spatial distribution of microglia in the damaged brain area.

Conclusion

TSPO-targeted PET using [¹⁸F]DPA-714 as the imaging probe can be used to dynamically monitor the inflammatory response after TBI in a noninvasive manner. This method will not only facilitate a better understanding of the inflammatory process after TBI, but also provide a useful in vivo monitoring strategy for antiinflammation therapy of TBI.     

Radiation dosimetry of the translocator protein ligands [18F]PBR111 and [18F]PBR102

IntroductionThe translocator protein (TSPO) ligands [¹⁸F]PBR111 and [¹⁸F]PBR102 show promise for imaging neuroinflammation. Our aim was to estimate the radiation dose to humans from primate positron emission tomography (PET) studies using these ligands and compare the results with those obtained from studies in rodents.Methods[¹⁸F]PBR111 and [¹⁸F]PBR102 PET–computed tomography studies were carried out in baboons. The cumulated activity in the selected source organs was obtained from the volume of interest time–activity curves drawn on coronal PET slices and adjusted for organ mass relative to humans. Radiation dose estimates were calculated in OLINDA/EXM Version 1.1 from baboon studies and compared with those calculated from Sprague–Dawley rat tissue concentration studies, also adjusted for relative organ mass.ResultsIn baboons, both ligands cleared rapidly from brain, lung, kidney and spleen and more slowly from liver and heart. For [¹⁸F]PBR111, the renal excretion fraction was 6.5% and 17% for hepatobiliary excretion; for [¹⁸F]PBR102, the renal excretion was 3.0% and 15% for hepatobiliary excretion. The estimated effective dose in humans from baboon data was 0.021 mSv/MBq for each ligand, whilst from rat data, the estimates were 0.029 for [¹⁸F]PBR111 and 0.041 mSv/MBq for [¹⁸F]PBR102.ConclusionBiodistribution in a nonhuman primate model is better suited than the rat model for the calculation of dosimetry parameters when translating these ligands from preclinical to human clinical studies. Effective dose calculated from rat data was overestimated compared to nonhuman primate data. The effective dose coefficient for both these TSPO ligands determined from PET studies in baboons is similar to that for [¹⁸F]FDG.     

Two activated stages of microglia and PET imaging of peripheral benzodiazepine receptors with [<Superscript>11</Superscript>C]PK11195 in rats

Objective  

The transition of microglia from the normal resting state to the activated state is associated with an increased expression of peripheral benzodiazepine receptors (PBR). The extent of PBR expression is dependent on the level of microglial activation. A PBR ligand, [¹¹C]PK11195, has been used for imaging of the activation of microglia in vivo. We evaluated whether [¹¹C]PK11195 PET can indicate differences of microglial activation between no treatment and lipopolysaccharide (LPS) treatment in a rat artificial injury model of brain inflammation.     

A Single Intraperitoneal Injection of Endotoxin Changes Glial Cells in Rats as Revealed by Positron Emission Tomography Using [<Superscript>11</Superscript>C]PK11195

Purpose

Intracranial administration of lipopolysaccharide (LPS) is known to elicit a rapid innate immune response, activate glial cells in the brain, and induce depression-like behavior. However, no study has focused on the changes in glial cells induced by intraperitoneal injection of LPS in vivo.

Methods

Ten adult male Fischer F344 rats underwent [¹¹C]PK11195 PET before and 2 days after intraperitoneal injection of LPS to evaluate the changes in glial cells. The difference in standardized uptake values (SUV) of [¹¹C]PK11195 between before and after injection was determined.

Results

There was a cluster of brain regions that showed significant reductions in SUV. This cluster included the bilateral striata and bilateral frontal regions, especially the somatosensory areas.

Conclusions

Changes in activity of glial cells induced by the intraperitoneal injection of LPS were detected in vivo by [¹¹C]PK11195 PET. Intraperitoneal injection of LPS is known to induce depression, and further studies with [¹¹C]PK11195 PET would clarify the relationships between neuroinflammation and depression.

     

Kinetic analysis of the translocator protein positron emission tomography ligand [<Superscript>18</Superscript>F]GE-180 in the human brain

Purpose

PET can image neuroinflammation by targeting the translocator protein (TSPO), which is upregulated in activated microglia. The high nonspecific binding of the first-generation TSPO radioligand [¹¹C]PK-11195 limits accurate quantification. [¹⁸F]GE-180, a novel TSPO ligand, displays superior binding to [¹¹C]PK-11195 in vitro. Our objectives were to: (1) evaluate tracer characteristics of [¹⁸F]GE-180 in the brains of healthy human subjects; and (2) investigate whether the TSPO Ala147Thr polymorphism influences outcome measures.

Methods

Ten volunteers (five high-affinity binders, HABs, and five mixed-affinity binders, MABs) underwent a dynamic PET scan with arterial sampling after injection of [¹⁸F]GE-180. Kinetic modelling of time–activity curves with one-tissue and two-tissue compartment models and Logan graphical analysis was applied to the data. The primary outcome measure was the total volume of distribution (V _T) across various regions of interest (ROIs). Secondary outcome measures were the standardized uptake values (SUV), the distribution volume and SUV ratios estimated using a pseudoreference region.

Results

The two-tissue compartment model was the best model. The average regional delivery rate constant (K ₁) was 0.01 mL cm^?3 min^?1 indicating low extraction across the blood–brain barrier (1 %). The estimated median V _T across all ROIs was also low, ranging from 0.16 mL cm^?3 in the striatum to 0.38 mL cm^?3 in the thalamus. There were no significant differences in V _T between HABs and MABs across all ROIs.

Conclusion

A reversible two-tissue compartment model fitted the data well and determined that the tracer has a low first-pass extraction (approximately 1 %) and low V _T estimates in healthy individuals. There was no observable dependency on the rs6971 polymorphism as compared to other second-generation TSPO PET tracers. Investigation of [¹⁸F]GE-180 in populations with neuroinflammatory disease is needed to determine its suitability for quantitative assessment of TSPO expression.

     

PET imaging of focal demyelination and remyelination in a rat model of multiple sclerosis: comparison of [11C]MeDAS, [11C]CIC and [11C]PIB

Purpose

In this study, we compared the ability of [¹¹C]CIC, [¹¹C]MeDAS and [¹¹C]PIB to reveal temporal changes in myelin content in focal lesions in the lysolecithin rat model of multiple sclerosis. Pharmacokinetic modelling was performed to determine the best method to quantify tracer uptake.

Methods

Sprague-Dawley rats were stereotactically injected with either 1 % lysolecithin or saline into the corpus callosum and striatum of the right brain hemisphere. Dynamic PET imaging with simultaneous arterial blood sampling was performed 7 days after saline injection (control group), 7 days after lysolecithin injection (demyelination group) and 4 weeks after lysolecithin injection (remyelination group).

Results

The kinetics of [¹¹C]CIC, [¹¹C]MeDAS and [¹¹C]PIB was best fitted by Logan graphical analysis, suggesting that tracer binding is reversible. Compartment modelling revealed that all tracers were fitted best with the reversible two-tissue compartment model. Tracer uptake and distribution volume in lesions were in agreement with myelin status. However, the slow kinetics and homogeneous brain uptake of [¹¹C]CIC make this tracer less suitable for in vivo PET imaging. [¹¹C]PIB showed good uptake in the white matter in the cerebrum, but [¹¹C]PIB uptake in the cerebellum was low, despite high myelin density in this region. [¹¹C]MeDAS distribution correlated well with myelin density in different brain regions.

Conclusion

This study showed that PET imaging of demyelination and remyelination processes in focal lesions is feasible. Our comparison of three myelin tracers showed that [¹¹C]MeDAS has more favourable properties for quantitative PET imaging of demyelinated and remyelinated lesions throughout the CNS than [¹¹C]CIC and [¹¹C]PIB.     

In vivo changes in microglial activation and amyloid deposits in brain regions with hypometabolism in Alzheimer��s disease

Purpose

Amyloid ?? protein (A??) is known as a pathological substance in Alzheimer??s disease (AD) and is assumed to coexist with a degree of activated microglia in the brain. However, it remains unclear whether these two events occur in parallel with characteristic hypometabolism in AD in vivo. The purpose of the present study was to clarify the in vivo relationship between A?? accumulation and neuroinflammation in those specific brain regions in early AD.

Methods

Eleven nootropic drug-na?ve AD patients underwent a series of positron emission tomography (PET) measurements with [¹¹C](R)PK11195, [¹¹C]PIB and [¹⁸F]FDG and a battery of cognitive tests within the same day. The binding potentials (BPs) of [¹¹C](R)PK11195 were directly compared with those of [¹¹C]PIB in the brain regions with reduced glucose metabolism.

Results

BPs of [¹¹C](R)PK11195 and [¹¹C]PIB were significantly higher in the parietotemporal regions of AD patients than in ten healthy controls. In AD patients, there was a negative correlation between dementia score and [¹¹C](R)PK11195 BPs, but not [¹¹C]PIB, in the limbic, precuneus and prefrontal regions. Direct comparisons showed a significant negative correlation between [¹¹C](R)PK11195 and [¹¹C]PIB BPs in the posterior cingulate cortex (PCC) (p?<?0.05, corrected) that manifested the most severe reduction in [¹⁸F]FDG uptake.

Conclusion

A lack of coupling between microglial activation and amyloid deposits may indicate that A?? accumulation shown by [¹¹C]PIB is not always the primary cause of microglial activation, but rather the negative correlation present in the PCC suggests that microglia can show higher activation during the production of A?? in early AD.     

Imaging of amyloid deposition in human brain using positron emission tomography and [18F]FACT: comparison with [11C]PIB

Purpose

The characteristic neuropathological changes in Alzheimer’s disease (AD) are deposition of amyloid senile plaques and neurofibrillary tangles. The ¹⁸F-labeled amyloid tracer, [¹⁸F]2-[(2-{(E)-2-[2-(dimethylamino)-1,3-thiazol-5-yl]vinyl}-1,3-benzoxazol-6-yl)oxy]-3-fluoropropan-1-ol (FACT), one of the benzoxazole derivatives, was recently developed. In the present study, deposition of amyloid senile plaques was measured by positron emission tomography (PET) with both [¹¹C]Pittsburgh compound B (PIB) and [¹⁸F]FACT in the same subjects, and the regional uptakes of both radiotracers were directly compared.

Methods

Two PET scans, one of each with [¹¹C]PIB and [¹⁸F]FACT, were performed sequentially on six normal control subjects, two mild cognitive impairment (MCI) patients, and six AD patients. The standardized uptake value ratio of brain regions to the cerebellum was calculated with partial volume correction using magnetic resonance (MR) images to remove the effects of white matter accumulation.

Results

No significant differences in the cerebral cortical uptake were observed between normal control subjects and AD patients in [¹⁸F]FACT studies without partial volume correction, while significant differences were observed in [¹¹C]PIB. After partial volume correction, the cerebral cortical uptake was significantly larger in AD patients than in normal control subjects for [¹⁸F]FACT studies as well as [¹¹C]PIB. Relatively lower uptakes of [¹¹C]PIB in distribution were observed in the medial side of the temporal cortex and in the occipital cortex as compared with [¹⁸F]FACT. Relatively higher uptake of [¹¹C]PIB in distribution was observed in the frontal and parietal cortices.

Conclusion

Since [¹⁸F]FACT might bind more preferentially to dense-cored amyloid deposition, regional differences in cerebral cortical uptake between [¹¹C]PIB and [¹⁸F]FACT might be due to differences in regional distribution between diffuse and dense-cored amyloid plaque shown in the autoradiographic and histochemical assays of postmortem AD brain sections.     

[11C]PIB, [18F]FDG and MR imaging in patients with mild cognitive impairment

Purpose

Cortical glucose metabolism, brain amyloid β accumulation and hippocampal atrophy imaging have all been suggested as potential biomarkers in predicting which patients with mild cognitive impairment (MCI) will convert to Alzheimer’s disease (AD). The aim of this study was to compare the prognostic ability of [¹¹C]PIB PET, [¹⁸F]FDG PET and quantitative hippocampal volumes measured with MR imaging in predicting conversion to AD in patients with MCI.

Methods

The study group comprised 29 patients with MCI who underwent [¹¹C]PIB PET and MR imaging. Of these, 22 also underwent [¹⁸F]FDG PET. All subjects were invited back for clinical evaluation after 2 years.

Results

During the follow-up time 17 patients had converted to AD while 12 continued to meet the criteria for MCI. The two groups did not differ in age, gender or education level, but the converter group tended to have lower MMSE and Word List learning than the nonconverter group. High [¹¹C]PIB retention in the frontotemporal regions and anterior and posterior cingulate (p?<?0.05) predicted conversion to AD. Also reduced [¹⁸F]FDG uptake in the left lateral temporal cortex (LTC) predicted conversion (p?<?0.05), but quantitative hippocampal volumes did not (p?>?0.1). In receiver operating characteristic (ROC) analysis the measurements that best predicted the conversion were [¹¹C]PIB retention in the lateral frontal cortex and [¹⁸F]FDG uptake in the left LTC. Both PET methods resulted in good sensitivity and specificity and neither was significantly superior to the other.

Conclusion

The findings indicate that [¹¹C]PIB and [¹⁸F]FDG are superior to hippocampal volumes in predicting conversion to AD in patients with MCI.     

[F]DPA-714, [F]PBR111 and [F]FEDAA1106—Selective radioligands for imaging TSPO 18 kDa with PET: Automated radiosynthesis on a TRACERLAb FX-FN synthesizer and quality controls

Imaging of TSPO 18 kDa with PET is more and more considered as a relevant biomarker of inflammation in numerous diseases. Development of new radiotracers for TSPO 18 kDa has seen acceleration in the last years and the challenge today is to make available large amounts of such a radiotracer in compliance with GMP standards for application in humans. We present in this technical note automated productions of [¹⁸F]DPA-714, [¹⁸F]PBR111 and [¹⁸F]FEDAA1106, three promising radiotracers for TSPO 18 kDa imaging, using a TRACERlab FX-FN synthesizer. This note also includes the quality control data of the validation batches for the manufacturing qualification of clinical production of [¹⁸F]DPA-714.     

Uptake of inflammatory cell marker [<Superscript>11</Superscript>C]PK11195 into mouse atherosclerotic plaques

Purpose  The ligand [¹¹C]PK11195 binds with high affinity and selectivity to peripheral benzodiazepine receptor, expressed in high amounts in macrophages. In humans, [¹¹C]PK11195 has been used successfully for the in vivo imaging of inflammatory processes of brain tissue. The purpose of this study was to explore the feasibility of [¹¹C]PK11195 in imaging inflammation in the atherosclerotic plaques. Methods  The presence of PK11195 binding sites in the atherosclerotic plaques was verified by examining the in vitro binding of [³H]PK11195 onto mouse aortic sections. Uptake of intravenously administered [¹¹C]PK11195 was studied ex vivo in excised tissue samples and aortic sections of a LDLR/ApoB48 atherosclerotic mice. Accumulation of the tracer was compared between the atherosclerotic plaques and non-atherosclerotic arterial sites by autoradiography and histological analyses. Results  The [³H]PK11195 was found to bind to both the atherosclerotic plaques and the healthy wall. The autoradiography analysis revealed that the uptake of [¹¹C]PK11195 to inflamed regions in plaques was more prominent (p = 0.011) than to non-inflamed plaque regions, but overall it was not higher than the uptake to the healthy vessel wall. Also, the accumulation of ¹¹C radioactivity into the aorta of the atherosclerotic mice was not increased compared to the healthy control mice. Conclusions  Our results indicate that the uptake of [¹¹C]PK11195 is higher in inflamed atherosclerotic plaques containing a large number of inflammatory cells than in the non-inflamed plaques. However, the tracer uptake to other structures of the artery wall was also prominent and may limit the use of [¹¹C]PK11195 in clinical imaging of atherosclerotic plaques.     

Evaluation of [11C]-DAA1106 for imaging and quantification of neuroinflammation in a rat model of herpes encephalitis

IntroductionMany neurological and psychiatric disorders are associated with neuroinflammation. Positron emission tomography (PET) with [¹¹C]-PK11195 can be used to study neuroinflammation in these disorders. However, [¹¹C]-PK11195 may not be sensitive enough to visualize mild neuroinflammation. As a potentially more sensitive PET tracer for neuroinflammation, [¹¹C]-N-(2,5-dimethoxybenzyl)-N-(4-fluoro-2-phenoxyphenyl)-acetamide (DAA1106) was evaluated in a rat model of herpes encephalitis.MethodsMale Wistar rats were intranasally inoculated with HSV-1 (HSE) or phosphate-buffered saline (control). At Day 6 or Day 7 after inoculation, small-animal [¹¹C]-DAA1106 PET scans were acquired, followed by ex vivo biodistribution. Arterial blood sampling was performed for quantification of uptake.ResultsIn HSE rats, a significantly higher ex vivo, but not in vivo, uptake of [¹¹C]-DAA1106 was found in almost all examined brain areas (24–71%, P<.05), when compared to control rats. Pretreatment with unlabeled PK11195 effectively reduced [¹¹C]-DAA1106 uptake in HSE rats (54–84%; P<.001). The plasma and brain time–activity curves showed rapid uptake of [¹¹C]-DAA1106 into tissue. The data showed a good fit to the Logan analysis but could not be fitted to a two-tissue compartment model.Conclusions[¹¹C]-DAA1106 showed a high and specific ex vivo uptake in the encephalitic rat brain. However, neuroinflammation could not be demonstrated in vivo by [¹¹C]-DAA1106 PET. Quantification of the uptake of [¹¹C]-DAA1106 using plasma sampling is not optimal, due to rapid tissue uptake, slow tissue clearance and low plasma activity.     

Visualising neuroinflammation in post-stroke patients: a comparative PET study with the TSPO molecular imaging biomarkers [11C]PK11195 and [11C]vinpocetine

With the main objective of comparing the prospective diagnostic power of two 11C-labelled molecular imaging biomarkers with affinity for TSPO and used for the visualisation of activated microglia after a stroke, we measured with positron emission tomography (PET) in four post-stroke patients the regional brain uptake and binding potential of [11C]vinpocetine and [11C]PK11195. Percentage standard uptake values (%SUV) and binding potential (BPND) were used as outcome measures. The total peak brain uptake value and average global brain uptake value were higher for [11C]vinpocetine than for [11C]PK11195. The regional %SUV values were significantly higher for [11C]vinpocetine than for [11C]PK11195 in the hemispheres as well as in almost all standard brain regions. The %SUV values of [11C]vinpocetine were higher in the peri-infarct zone than in the ischaemic core, however, the difference did not prove to be significant. There was basically no difference in %SUV values between the ischaemic core and the peri-infarct zone for [11C]PK11195. The BPND values for [11C]vinpocetine were higher in all standard regions than those for [11C]PK11195, but the difference was not significant between them. The BPND values of [11C]vinpocetine were higher in the peri-infarct zone than in the ischaemic core, however, the difference did not prove to be significant. A comparative analysis of the two ligands indicates that [11C]vinpocetine shows a number of favourable characteristics over [11C]PK11195, but to demonstrate that it may serve as a prospective molecular imaging biomarker of microglia activation in post-stroke patients, further studies are required.     

In vivo imaging of the 18-kDa translocator protein (TSPO) with [18F]FEDAA1106 and PET does not show increased binding in Alzheimer’s disease patients

Purpose

Imaging the 18-kDa translocator protein (TSPO) is considered a potential tool for in vivo evaluation of microglial activation and neuroinflammation in the early stages of Alzheimer’s disease (AD). ((R)-1-(2-chlorophenyl)-N-[¹¹C]-methyl-N-(1-methylpropyl)-3-isoquinoline caboxamide ([¹¹C]-(R)-PK11195) has been widely used for PET imaging of TSPO and, despite its low specific-to-nondisplaceable binding ratio, increased TSPO binding has been shown in AD patients. The high-affinity radioligand N-(5-fluoro-2-phenoxyphenyl)-N-(2-[¹⁸F]fluoroethyl-5-methoxybenzyl)acetamide ([¹⁸F]FEDAA1106) has been developed as a potential in vivo imaging tool for better quantification of TSPO binding. The aim of this study was to quantify in vivo binding of [¹⁸F]FEDAA1106 to TSPO in control subjects and AD patients.

Methods

Seven controls (five men, two women, age 68±3 years, MMSE score 29±1) and nine AD patients (six men, three women, age 69±4 years, MMSE score 25±3) were studied with [¹⁸F]FEDAA1106. PET measurements were performed on an ECAT EXACT HR system (Siemens Medical Solutions) in two 60-min dynamic PET sessions with a 30-min interval between sessions. Arterial blood radioactivity was measured using an automated blood sampling system for the first 5 min and using manually drawn samples thereafter. Quantification was performed using both kinetic analysis based on a two-tissue compartment model and Logan graphical analysis. Outcome measures were total distribution volume (V _T) and binding potential (BP _ND=k ₃/k ₄). An estimate of nondisplaceable distribution volume was obtained with the Logan graphical analysis using the first 15 min of PET measurements (V _{ND 1-15 min}). Binding potential (BP _ND) was also calculated as: V _T/V _{ND 1-15 min} ? 1.

Results

No statistically significant differences in V _T, k ₃/k ₄ or BP _ND were observed between controls and AD patients.

Conclusion

This study suggests that TSPO imaging with [¹⁸F]FEDAA1106 does not enable the detection of microglial activation in AD.     

Human biodistribution and radiation dosimetry of 11C-(R)-PK11195, the prototypic PET ligand to image inflammation

Purpose  

The positron emission tomography (PET) radiotracer ¹¹C-(R)-PK11195 allows the in vivo imaging in humans of the translocator protein 18 kDa (TSPO), previously called peripheral benzodiazepine receptor (PBR), a marker of inflammation. Despite its widespread use, the radiation burden associated with ¹¹C-(R)-PK11195 in humans is not known. To examine this, we performed dynamic whole-body imaging with PET and ¹¹C-(R)-PK11195 in healthy humans.