Novel plasma protein binding analysis method for a PET tracer and its radiometabolites: A case study with [11C]SMW139 to explain the high uptake of radiometabolites in mouse brain

Aarnio, Richard; Alzghool, Obada M.; Wahlroos, Saara; O'Brien-Brown, James; Kassiou, Michael; Solin, Olof; Rinne, Juha O.; Forsbäck, Sarita; Haaparanta‐Solin, Merja

doi:10.1016/j.jpba.2022.114860

Cited by 8 publications

(9 citation statements)

References 23 publications

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“…Defining the time frame for quantifying [ 11 C]SMW139 in vivo uptake was complicated by the fast metabolic profile in mice, and the presence of radioactive metabolites in the brain tissue. In a previous study with [ 11 C]SMW139, we detected up to three brain penetrant radiometabolites of [ 11 C]SMW139 in mouse brain homogenates and one radiometabolite more in plasma already at 10 min after tracer injection [ 32 ]; similar findings were also reported by Brumberg and colleagues [ 42 ]. Accordingly, an appropriate time frame needs to be selected in which there is still a reasonable percentage of the parent fraction and as little interference as possible from the radiometabolite fraction.…”

Section: Discussionsupporting

confidence: 83%

“…The radiotracers [ 11 C]SMW139 (2-chloro-5-[ 11 C]methoxy- N -((3,5,7-trifluoroadamantan-1-yl)methyl)benzamide) and [ 18 F]F-DPA ( N , N -diethyl-2-(2-(4-([ 18 F]fluoro)phenyl)-5,7-dimethylpyrazolo[1,5-a] pyrimidin-3-yl)acetamide) were produced in the radiopharmaceutical laboratory at Turku PET Centre as described previously [ 32 , 33 ]. For the 32 batches of [ 11 C]SMW139, the molar activity was 33.0 (21.0) GBq/µmol at the time of injection, radiochemical purity 98.3% (0.5%), and radiotracer shelf-life 1 h. For the three batches of [ 18 F]F-DPA, the molar activity was 3.2 (0.6) GBq/µmol at the time of injection, radiochemical purity > 99%, and radiotracer shelf-life at least 4 h.…”

Section: Methodsmentioning

confidence: 99%

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Glial reactivity in a mouse model of beta-amyloid deposition assessed by PET imaging of P2X7 receptor and TSPO using [11C]SMW139 and [18F]F-DPA

Alzghool,

Aarnio,

Helin

et al. 2024

EJNMMI Res

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Background P2X7 receptor has emerged as a potentially superior PET imaging marker to TSPO, the gold standard for imaging glial reactivity. [11C]SMW139 is the most recently developed radiotracer to image P2X7 receptor. The aim of this study was to image reactive glia in the APP/PS1-21 transgenic (TG) mouse model of Aβ deposition longitudinally using [11C]SMW139 targeting P2X7 receptor and to compare tracer uptake to that of [18F]F-DPA targeting TSPO at the final imaging time point. TG and wild type (WT) mice underwent longitudinal in vivo PET imaging using [11C]SMW139 at 5, 8, 11, and 14 months, followed by [18F]F-DPA PET scan only at 14 months. In vivo imaging results were verified by ex vivo brain autoradiography, immunohistochemical staining, and analysis of [11C]SMW139 unmetabolized fraction in TG and WT mice. Results Longitudinal change in [11C]SMW139 standardized uptake values (SUVs) showed no statistically significant increase in the neocortex and hippocampus of TG or WT mice, which was consistent with findings from ex vivo brain autoradiography. Significantly higher [18F]F-DPA SUVs were observed in brain regions of TG compared to WT mice. Quantified P2X7-positive staining in the cortex and thalamus of TG mice showed a minor increase in receptor expression with ageing, while TSPO-positive staining in the same regions showed a more robust increase in expression in TG mice as they aged. [11C]SMW139 was rapidly metabolized in mice, with 33% of unmetabolized fraction in plasma and 29% in brain homogenates 30 min after injection. Conclusions [11C]SMW139, which has a lower affinity for the rodent P2X7 receptor than the human version of the receptor, was unable to image the low expression of P2X7 receptor in the APP/PS1-21 mouse model. Additionally, the rapid metabolism of [11C]SMW139 in mice and the presence of several brain-penetrating radiometabolites significantly impacted the analysis of in vivo PET signal of the tracer. Finally, [18F]F-DPA targeting TSPO was more suitable for imaging reactive glia and neuroinflammatory processes in the APP/PS1-21 mouse model, based on the findings presented in this study and previous studies with this mouse model.

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Section: Discussionsupporting

confidence: 83%

Section: Methodsmentioning

confidence: 99%

Glial reactivity in a mouse model of beta-amyloid deposition assessed by PET imaging of P2X7 receptor and TSPO using [11C]SMW139 and [18F]F-DPA

Alzghool,

Aarnio,

Helin

et al. 2024

EJNMMI Res

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“…Eleven C57BL/6J mice were examined with [ 11 C]SMW139 (all female; weight: 34 ± 4 g; age: 8.7 ± 1.9 months; injected activity: 17.9 ± 6.2 MBq; molar activity: 42.2 ± 24.1 MBq/nmol; injected mass: 0.21 ± 0.12 µg; for radiochemistry see Supplemental methods 13 , 14 ). Ex vivo sampling for parent fraction analysis was performed at 10 min ( n = 4), 30 min (n = 3) and 45 min (n = 4) post radioligand injection (p.i.)…”

Section: Methodsmentioning

confidence: 99%

Quantification of the purinergic P2X₇ receptor with [¹¹C]SMW139 improves through correction for brain-penetrating radiometabolites

Brumberg

Aarnio

Forsberg

et al. 2022

J Cereb Blood Flow Metab

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The membrane-based purinergic 7 receptor (P2X7R) is expressed on activated microglia and the target of the radioligand [11C]SMW139 for in vivo assessment of neuroinflammation. This study investigated the contribution of radiolabelled metabolites which potentially affect its quantification. Ex vivo high-performance liquid chromatography with a radio detector (radioHPLC) was used to evaluate the parent and radiometabolite fractions of [11C]SMW139 in the brain and plasma of eleven mice. Twelve healthy humans underwent 90-min [11C]SMW139 brain PET with arterial blood sampling and radiometabolite analysis. The volume of distribution was estimated by using one- and two- tissue compartment (TCM) modeling with single ( VT) and dual ( VTp) input functions. RadioHPLC showed three major groups of radiometabolite peaks with increasing concentrations in the plasma of all mice and humans. Two radiometabolite peaks were also visible in mice brain homogenates and therefore considered for dual input modeling in humans. 2TCM with single input function provided VT estimates with a wide range (0.10–10.74) and high coefficient of variation (COV: 159.9%), whereas dual input function model showed a narrow range of VTp estimates (0.04–0.24; COV: 33.3%). In conclusion, compartment modeling with correction for brain-penetrant radiometabolites improves the in vivo quantification of [11C]SMW139 binding to P2X7R in the human brain.

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“…Key exclusion criteria included pregnancy, claustrophobia, and other signi cant central nervous system pathology besides MS. All MS patients underwent baseline neurological assessments, magnetic resonance imaging (MRI) and [ 11 C]SMW139 production and PET Irradiations were performed with a TR-19 (ACSI, Richmond, Canada) cyclotron to produce the carbon-11 radioisotope according to previously described procedures [8]. The complete synthesis procedure of [ 11 C]SMW139 at the Radiopharmaceutical Chemistry Laboratory of Turku PET Centre is described in the supplementary material of Aarnio et al 2022 [24].…”

Section: Subjects and Proceduresmentioning

confidence: 99%

P2X7-receptor binding in new-onset and secondary progressive MS – a [11C]SMW139 PET study

Lehto,

Aarnio,

Tuisku

et al. 2024

Preprint

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Background PET imaging of activated microglia has improved our understanding of the pathology behind disability progression in MS, and pro-inflammatory microglia at ‘smoldering’ lesion rims have been implicated as drivers of disability progression. The P2X7R is upregulated in the cellular membranes of activated microglia. A single-tissue dual-input model was applied to quantify P2X7R binding in the normal appearing white matter, perilesional areas and thalamus among progressive MS patients, healthy controls and newly diagnosed relapsing MS patients. Results Overall, tracer uptake in the MS brain was not significantly higher compared to HCs. In the 3 mm perilesional rim of all T1 lesions, tracer binding was higher among relapsing patients compared to progressive patients. Tracer binding was higher in males compared to females. Disease duration correlated with tracer binding in the normal appearing white matter. Age correlated negatively with tracer binding in the perilesional rims. Conclusions Binding estimates obtained with the dual-input model were consistent with the expected distribution of P2X7Rs in the MS brain. According to our study, [11C]SMW139-binding may capture a glial cell phenotype significant in early development of chronic active lesions in relapsing stages of MS. Only tentative evidence for the applicability of [11C]SMW139 to detect MS-related diffuse smoldering inflammation was obtained.

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Novel plasma protein binding analysis method for a PET tracer and its radiometabolites: A case study with [11C]SMW139 to explain the high uptake of radiometabolites in mouse brain

Cited by 8 publications

References 23 publications

Glial reactivity in a mouse model of beta-amyloid deposition assessed by PET imaging of P2X7 receptor and TSPO using [11C]SMW139 and [18F]F-DPA

Glial reactivity in a mouse model of beta-amyloid deposition assessed by PET imaging of P2X7 receptor and TSPO using [11C]SMW139 and [18F]F-DPA

Quantification of the purinergic P2X₇ receptor with [¹¹C]SMW139 improves through correction for brain-penetrating radiometabolites

P2X7-receptor binding in new-onset and secondary progressive MS – a [11C]SMW139 PET study

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Novel plasma protein binding analysis method for a PET tracer and its radiometabolites: A case study with [11C]SMW139 to explain the high uptake of radiometabolites in mouse brain

Cited by 8 publications

References 23 publications

Glial reactivity in a mouse model of beta-amyloid deposition assessed by PET imaging of P2X7 receptor and TSPO using [11C]SMW139 and [18F]F-DPA

Glial reactivity in a mouse model of beta-amyloid deposition assessed by PET imaging of P2X7 receptor and TSPO using [11C]SMW139 and [18F]F-DPA

Quantification of the purinergic P2X7 receptor with [11C]SMW139 improves through correction for brain-penetrating radiometabolites

P2X7-receptor binding in new-onset and secondary progressive MS – a [11C]SMW139 PET study

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Quantification of the purinergic P2X₇ receptor with [¹¹C]SMW139 improves through correction for brain-penetrating radiometabolites