Synthesis and Structure–Affinity Relationship of Small Molecules for Imaging Human CD80 by Positron Emission Tomography

Taddio, Marco F.; Mu, Linjing; Jaramillo, Claudia A. Castro; Bollmann, Tanja; Schmid, Dominik; Muskalla, Lukas; Gruene, Tim; Chiotellis, Aristeidis; Ametamey, Simon M.; Schibli, Roger; Krämer, Stefanie-Dorothea

doi:10.1021/acs.jmedchem.9b00858

Cited by 9 publications

(8 citation statements)

References 30 publications

(125 reference statements)

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“…In general, distribution should be equilibrated for constant signal ratios between target-rich and reference (low or no target) region. The earliest time point for quantitative imaging after injection of labelled abatacept in mice is thus 24 h. We chose 48 h to guarantee equilibrated distribution and as 48 h provided better imaging results than 18 h in our former study with the related protein 111 In-DOTA-belatacept [20,21]. For labelling, we chose Cu-64 as it provides high spatial resolution due to its low decay energy (0.7 mm mean range in water before annihilation) and as 64 Cu-NODAGA complexes have an excellent stability in vivo [36][37][38].…”

Section: Discussionmentioning

confidence: 99%

“…To shorten the time between tracer administration and imaging and to potentially reduce biological effects which may result in adverse clinical effects besides biasing the imaging results, we are currently evaluating optimised protein tracers (Castro et al, unpublished) and are developing small molecule PET tracers selectively targeting hCD80 [21,41]. 64 Cu-NODAGA-abatacept binds to both CD80 and CD86 with strong affinity.…”

Section: Discussionmentioning

confidence: 99%

“…S5 shows higher binding of 64 Cu-NODAGA-abatacept to slices of Raji (hCD80 + Burkitt's lymphoma cells) than NCI-H69 (hCD80small cell lung carcinoma cells) xenografts. Coincubation with an excess of the small molecule hCD80 inhibitor MT107 [21] or non-conjugated abatacept reduced 64 Cu-NODAGA-abatacept binding to the Raji slices, indicating that the accumulation of tracer in the hCD80-rich tissue was specific. Fig.…”

Section: Production and In Vitro Characterisation Of 64 Cu-nodaga-abamentioning

confidence: 99%

“…This could be of interest for staging infections, Toll-like receptor-4 (TLR-4)-induced inflammation, autoimmune processes, transplant rejection and for monitoring the effects of cancer immunotherapy [12][13][14][15][16][17][18][19]. Our group has recently evaluated 111 In-DOTA-belatacept and small molecule inhibitors of human CD80 (hCD80) as SPECT and PET tracers, respectively, for imaging CD80/CD86 in a CD80-positive xenograft mouse model [20,21].…”

Section: Introductionmentioning

confidence: 99%

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In Vivo Imaging of Local Inflammation: Monitoring LPS-Induced CD80/CD86 Upregulation by PET

et al. 2020

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Purpose The co-stimulatory molecules CD80 and CD86 are upregulated on activated antigen-presenting cells (APC). We investigated whether local APC activation, induced by subcutaneous (s.c.) inoculation of lipopolysaccharides (LPS), can be imaged by positron emission tomography (PET) with CD80/CD86-targeting 64Cu-labelled abatacept. Procedures Mice were inoculated s.c. with extracellular-matrix gel containing either LPS or vehicle (PBS). Immune cell populations were analysed by flow cytometry and marker expression by RT-qPCR. 64Cu-NODAGA-abatacept distribution was analysed using PET/CT and ex vivo biodistribution. Results The number of CD80+ and CD86+ immune cells at the LPS inoculation site significantly increased a few days after inoculation. CD68 and CD86 expression were higher at the LPS than the PBS inoculation site, and CD80 was only increased at the LPS inoculation site. CTLA-4 was highest 10 days after LPS inoculation, when CD80/CD86 decreased again. A few days after inoculation, 64Cu-NODAGA-abatacept distribution to the inoculation site was significantly higher for LPS than PBS (4.2-fold). Co-administration of unlabelled abatacept or human immunoglobulin reduced tracer uptake. The latter reduced the number of CD86+ immune cells at the LPS inoculation site. Conclusions CD80 and CD86 are upregulated in an LPS-induced local inflammation, indicating invasion of activated APCs. 64Cu-NODAGA-abatacept PET allowed following APC activation over time.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Production and In Vitro Characterisation Of 64 Cu-nodaga-abamentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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In Vivo Imaging of Local Inflammation: Monitoring LPS-Induced CD80/CD86 Upregulation by PET

et al. 2020

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“…For the evaluation of plasma protein binding, 45 55.5 MBq radiotracer was added to 150 μL of plasma, which was pre-incubated under 37 o C for 5 min (n = 3). The samples were incubated at 37 o C for 10 min.…”

Section: Plasma Protein Bindingmentioning

confidence: 99%

Radiosynthesis and preclinical evaluation of a carbon-11 labeled PDE7 inhibitor for PET neuroimaging

Xiao¹,

Sun²,

Fujinaga

et al. 2021

Preprint

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BackgroundDysfunction of cyclic nucleotide phosphodiesterase 7 (PDE7) has been associated with excess intracellular cAMP concentrations, fueling pathogenic processes that are implicated in neurodegenerative disorders. The aim of this study was to develop a suitable PDE7-targeted positron emission tomography (PET) probe that allows non-invasive mapping of PDE7 in the mammalian brain.MethodsBased on a spiro cyclohexane-1,4’-quinazolinone scaffold with known inhibitory properties towards PDE7, we designed and synthesized a methoxy analog that was suitable for carbon-11 labeling. Radiosynthesis was conducted with the respective desmethyl precursor using [11C]MeI. The resulting PET probe, codenamed [11C]26, was evaluated by cell uptake studies, ex vivo biodistribution and radiometabolite studies, as well as in vivo PET experiments in rodents and nonhuman primates (NHP).ResultsTarget compound 26 and the corresponding phenolic precursor were synthesized in 2-3 steps with overall yields of 49.5% and 12.4%, respectively. An inhibitory constant (IC50) of 31 nM towards PDE7 was obtained and no significant interaction with other PDE isoforms were observed. [11C]26 was synthesized in high molar activities (170 - 220 GBq/μmol) with radiochemical yields of 34±7%. In vitro cell uptake of [11C]26 was 6-7 folds higher in PDE7 overexpressing cells, as compared to the controls, whereas an in vitro specificity of up to 90% was measured. Ex vivo metabolite studies revealed a high fraction of intact parent in the rat brain (98% at 5 min and 75% at 30 min post injection). Considerable brain penetration was further corroborated by ex vivo biodistribution and PET imaging studies – the latter showing heterogenic brain uptake. While marginal specific binding was observed by PET studies in rodents, a moderate, but dose-dependent, blockade was observed in the NHP brain following pretreatment with non-radioactive 26.ConclusionIn this work, we report on the preclinical evaluation of [11C]26 (codename [11C]P7-2104), a PDE7-targeted PET ligand that is based on a spiroquinazolinone scaffold. [11C]26 displayed promising in vitro performance characteristics, a moderate degree of specific binding in PET studies with NHP. Accordingly, [11C]26 will serve as a valuable lead compound for the development of a new arsenal of PDE7-targeted probes with potentially improved in vivo specificity.

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Preclinical Evaluation of the Reversible Monoacylglycerol Lipase PET Tracer (R)‐[¹¹C]YH132: Application in Drug Development and Neurodegenerative Diseases

He,

Delparente,

Jie

et al. 2024

ChemBioChem

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Monoacylglycerol lipase (MAGL) plays a crucial role in the degradation of 2‐arachidonoylglycerol (2‐AG), one of the major endocannabinoids in the brain. Inhibiting MAGL could lead to increased levels of 2‐AG, which showed beneficial effects on pain management, anxiety, inflammation, and neuroprotection. In the current study, we report the characterization of an enantiomerically pure (R)‐[11C]YH132 as a novel MAGL PET tracer. It demonstrates an improved pharmacokinetic profile compared to its racemate. High in vitro MAGL specificity of (R)‐[11C]YH132 was confirmed by autoradiography studies using mouse and rat brain sections. In vivo, (R)‐[11C]YH132 displayed a high brain penetration, and high specificity and selectivity toward MAGL by dynamic PET imaging using MAGL knockout and wild‐type mice. Pretreatment with a MAGL drug candidate revealed a dose‐dependent reduction of (R)‐[11C]YH132 accumulation in WT mouse brains. This result validates its utility as a PET probe to assist drug development. Moreover, its potential application in neurodegenerative diseases was explored by in vitro autoradiography using brain sections from animal models of Alzheimer's disease and Parkinson's disease.

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Synthesis and Structure–Affinity Relationship of Small Molecules for Imaging Human CD80 by Positron Emission Tomography

Cited by 9 publications

References 30 publications

In Vivo Imaging of Local Inflammation: Monitoring LPS-Induced CD80/CD86 Upregulation by PET

In Vivo Imaging of Local Inflammation: Monitoring LPS-Induced CD80/CD86 Upregulation by PET

Radiosynthesis and preclinical evaluation of a carbon-11 labeled PDE7 inhibitor for PET neuroimaging

Preclinical Evaluation of the Reversible Monoacylglycerol Lipase PET Tracer (R)‐[¹¹C]YH132: Application in Drug Development and Neurodegenerative Diseases

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Synthesis and Structure–Affinity Relationship of Small Molecules for Imaging Human CD80 by Positron Emission Tomography

Cited by 9 publications

References 30 publications

In Vivo Imaging of Local Inflammation: Monitoring LPS-Induced CD80/CD86 Upregulation by PET

In Vivo Imaging of Local Inflammation: Monitoring LPS-Induced CD80/CD86 Upregulation by PET

Radiosynthesis and preclinical evaluation of a carbon-11 labeled PDE7 inhibitor for PET neuroimaging

Preclinical Evaluation of the Reversible Monoacylglycerol Lipase PET Tracer (R)‐[11C]YH132: Application in Drug Development and Neurodegenerative Diseases

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Preclinical Evaluation of the Reversible Monoacylglycerol Lipase PET Tracer (R)‐[¹¹C]YH132: Application in Drug Development and Neurodegenerative Diseases