Comparison of in vivo binding properties of the 18-kDa translocator protein (TSPO) ligands [18F]PBR102 and [18F]PBR111 in a model of excitotoxin-induced neuroinflammation

Callaghan, Paul D.; Wimberley, Catriona; Rahardjo, Gita; Berghofer, Paula; Pham, Tien; Jackson, Timothy; Zahra, David; Bourdier, Thomas; Wyatt, Naomi; Greguric, Ivan; Howell, Nicholas R.; Siegele, Rainer; Pastuović, Željko; Mattner, Filomena; Loc’h, Christian; Grégoire, Marie Claude; Katsifis, Andrew

doi:10.1007/s00259-014-2895-3

Cited by 10 publications

(8 citation statements)

References 39 publications

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“…CB251 was next assayed for its binding affinity to TSPO and CBR by measuring its ability to displace [ 3 H]PK 11195 and [ 3 H]flunitrazepam, respectively 24 . As shown in Table 2 , the affinities for TSPO and CBR, expressed as inhibition constants (K i ), were compared with those of unlabelled PK 11195, PBR28 and flunitrazepam.…”

Section: Resultsmentioning

confidence: 99%

“…Thus, radioligands from imidazopyridine and other structural classes with improved in vivo specificity for TSPO and with the potential to improve PET imaging of TSPO expression have been synthesized and evaluated in animals 22 23 . Recently, the first examples of 18 F-labelled alpidem analogues, also known as [ 18 F]PBR102 and [ 18 F]PBR111, have been assessed in vivo using PET 23 24 . Alpidem has been shown to act on both TSPO and central benzodiazepine receptors (CBRs), with a preference towards TSPO.…”

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confidence: 99%

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A Novel PET Imaging Probe for the Detection and Monitoring of Translocator Protein 18 kDa Expression in Pathological Disorders

Perrone

Moon

Park

et al. 2016

Sci Rep

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A new fluorine-substituted ligand, compound 1 (CB251), with a very high affinity (Ki = 0.27 ± 0.09 nM) and selectivity for the 18-kDa translocator protein (TSPO), is presented as an attractive biomarker for the diagnosis of neuroinflammation, neurodegeneration and tumour progression. To test compound 1 as a TSPO PET imaging agent in vivo, 2-(2-(4-(2-[18F]fluoroethoxy)phenyl)-6,8-dichloroimidazo[1,2-a]pyridin-3-yl)-N,N-dipropylacetamide ([18F]1; [18F]CB251) was synthesized by nucleophilic aliphatic substitution in a single-step radiolabelling procedure with a 11.1 ± 3.5% (n = 14, decay corrected) radiochemical yield and over 99% radiochemical purity. In animal PET imaging studies, [18F]CB251 provided a clearly visible image of the inflammatory lesion with the binding potential of the specifically bound radioligand relative to the non-displaceable radioligand in tissue (BPND 1.83 ± 0.18), in a neuroinflammation rat model based on the unilateral stereotaxic injection of lipopolysaccharide (LPS), comparable to that of [11C]PBR28 (BPND 1.55 ± 0.41). [18F]CB251 showed moderate tumour uptake (1.96 ± 0.11%ID/g at 1 h post injection) in human glioblastoma U87-MG xenografts. These results suggest that [18F]CB251 is a promising TSPO PET imaging agent for neuroinflammation and TSPO-rich cancers.

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Section: Resultsmentioning

confidence: 99%

mentioning

confidence: 99%

A Novel PET Imaging Probe for the Detection and Monitoring of Translocator Protein 18 kDa Expression in Pathological Disorders

Perrone

Moon

Park

et al. 2016

Sci Rep

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“…While blood sampling was not permitted in the macaques, blood, brain and other tissue sampling in rats allowed the evaluation of the formation of radioactive metabolites. ( S )-[ 18 F]GE387 had a better metabolite profile than ( R )-[ 18 F]GE387 in the plasma, which at 28% at 60 min post-injection is similar to [ 18 F]GE180 (21 ± 4.6%) [ 22 ] and [ 18 F]PBR111 (20%) [ 23 ]. ( S )-[ 18 F]GE387 had slower metabolism than ( R )-[ 18 F]GE387 and also had lower levels of radiometabolites in the brain at the end of the 60-min scan.…”

Section: Discussionmentioning

confidence: 98%

Preclinical evaluation of (S)-[18F]GE387, a novel 18-kDa translocator protein (TSPO) PET radioligand with low binding sensitivity to human polymorphism rs6971

Ramakrishnan

Hird

Thompson

et al. 2021

Eur J Nucl Med Mol Imaging

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Purpose Positron emission tomography (PET) studies with radioligands for 18-kDa translocator protein (TSPO) have been instrumental in increasing our understanding of the complex role neuroinflammation plays in disorders affecting the brain. However, (R)-[11C]PK11195, the first and most widely used TSPO radioligand has limitations, while the next-generation TSPO radioligands have suffered from high interindividual variability in binding due to a genetic polymorphism in the TSPO gene (rs6971). Herein, we present the biological evaluation of the two enantiomers of [18F]GE387, which we have previously shown to have low sensitivity to this polymorphism. Methods Dynamic PET scans were conducted in male Wistar rats and female rhesus macaques to investigate the in vivo behaviour of (S)-[18F]GE387 and (R)-[18F]GE387. The specific binding of (S)-[18F]GE387 to TSPO was investigated by pre-treatment with (R)-PK11195. (S)-[18F]GE387 was further evaluated in a rat model of lipopolysaccharide (LPS)-induced neuroinflammation. Sensitivity to polymorphism of (S)-GE387 was evaluated in genotyped human brain tissue. Results (S)-[18F]GE387 and (R)-[18F]GE387 entered the brain in both rats and rhesus macaques. (R)-PK11195 blocked the uptake of (S)-[18F]GE387 in healthy olfactory bulb and peripheral tissues constitutively expressing TSPO. A 2.7-fold higher uptake of (S)-[18F]GE387 was found in the inflamed striatum of LPS-treated rodents. In genotyped human brain tissue, (S)-GE387 was shown to bind similarly in low affinity binders (LABs) and high affinity binders (HABs) with a LAB to HAB ratio of 1.8. Conclusion We established that (S)-[18F]GE387 has favourable kinetics in healthy rats and non-human primates and that it can distinguish inflamed from normal brain regions in the LPS model of neuroinflammation. Crucially, we have reconfirmed its low sensitivity to the TSPO polymorphism on genotyped human brain tissue. Based on these factors, we conclude that (S)-[18F]GE387 warrants further evaluation with studies on human subjects to assess its suitability as a TSPO PET radioligand for assessing neuroinflammation.

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“…Further, the induction of TSPO paralleled and co-localized with the expression of proinflammatory and anti-inflammatory microglial markers, CD16/32 and CD206, respectively further emphasizing a possible functional role of TSPO in brain inflammatory responses after ICH (Bonsack et al, 2016 ). Though the precise role of TSPO in microglial/macrophage functions after brain pathology remains largely unknown, the radio labeled ligands of TSPO are widely being tested for its ability to assess brain inflammation (Callaghan et al, 2015 ; Damont et al, 2015 ; Liu et al, 2015 ; Loth et al, 2016 ; Alam et al, 2017 ; Crawshaw and Robertson, 2017 ; Fujita et al, 2017 ; Ishikawa et al, 2018 ). However, until very recently no such effort has been made after ICH.…”

Section: Can Tspo Be Targeted For Neuroimaging After Ich?mentioning

confidence: 99%

[125 I]IodoDPA-713 Binding to 18 kDa Translocator Protein (TSPO) in a Mouse Model of Intracerebral Hemorrhage: Implications for Neuroimaging

et al. 2018

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Intracerebral hemorrhage (ICH) is a fatal stroke subtype with significant public health impact. Although neuroinflammation is a leading cause of neurological deficits after ICH, no imaging tool is currently available to monitor brain inflammation in ICH patients. Given the role of TSPO in neuroinflammation, herein we investigate whether a second-generation TSPO ligand, [125 I]IodoDPA-713 can be used to monitor the changes in TSPO expression in a preclinical model of intracerebral hemorrhage. Male CD1 mice were subjected to ICH/Sham. The brain sections, collected at different time points were incubated with [125 I]IodoDPA-713 and the brain uptake of [125 I]IodoDPA-713 was estimated using autoradiography. The specificity of [125 I]IodoDPA-713 binding was confirmed by a competitive displacement study with an unlabeled TSPO ligand, PK11195. [125 I]IodoDPA-713 binding was higher in the ipsilateral striatum with an enhanced binding observed in the peri-hematomal brain region after ICH, whereas the brain sections from sham as well as contralateral brain areas of ICH exhibited marginal binding of [125 I]IodoDPA-713. PK11195 completely reversed the [125 I] IodoDPA-713 binding to brain sections suggesting a specific TSPO-dependent binding of [125 I]IodoDPA-713 after ICH. This was further confirmed with immunohistochemistry analysis of adjacent sections, which revealed a remarkable expression of TSPO in the areas of high [125 I]IodoDPA-713 binding after ICH. The specific as well as enhanced binding of [125 I]IodoDPA-713 to the ipsilateral brain areas after ICH as assessed by autoradiography analysis provides a strong rationale for testing the applicability of [125 I]IodoDPA-713 for non-invasive neuroimaging in preclinical models of ICH.

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Comparison of in vivo binding properties of the 18-kDa translocator protein (TSPO) ligands [18F]PBR102 and [18F]PBR111 in a model of excitotoxin-induced neuroinflammation

Cited by 10 publications

References 39 publications

A Novel PET Imaging Probe for the Detection and Monitoring of Translocator Protein 18 kDa Expression in Pathological Disorders

A Novel PET Imaging Probe for the Detection and Monitoring of Translocator Protein 18 kDa Expression in Pathological Disorders

Preclinical evaluation of (S)-[18F]GE387, a novel 18-kDa translocator protein (TSPO) PET radioligand with low binding sensitivity to human polymorphism rs6971

[125 I]IodoDPA-713 Binding to 18 kDa Translocator Protein (TSPO) in a Mouse Model of Intracerebral Hemorrhage: Implications for Neuroimaging

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