Synthesis and preclinical evaluation of the CRTH2 antagonist [11C]MK-7246 as a novel PET tracer and potential surrogate marker for pancreatic beta-cell mass

Eriksson, Jonas; Roy, Tamal; Sawadjoon, Supaporn; Bachmann, Kim; Sköld, Christian; Larhed, Mats; Weis, Ján; Selvaraju, Ram Kumar; Korsgren, Olle; Eriksson, Olof; Odell, Luke R.

doi:10.1016/j.nucmedbio.2019.04.002

Cited by 11 publications

(11 citation statements)

References 21 publications

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“…Similar results were seen for 3 H-AZ12204657 on human pancreatic sections from non-diabetic donors [30••]. 11 C-MK-7246 also bound in clear focal patterns to human pancreatic sections from non-diabetic and T2D donors, which was likely receptor-mediated as it could be abolished by co-incubation with unlabeled MK-7246 added in excess [36••]. The focal patterns were dense especially in areas positive for insulin staining.…”

Section: Imaging Results—in Vitro Approachessupporting

confidence: 61%

“…The splenic binding is not expected to occur in humans in vivo, based on in vitro autoradiographic studies of human splenic sections [38••]. 11 C-MK-7246 was evaluated in pigs by PET/CT, where significant binding similarly was seen in pancreas and spleen [36••]. The binding was reduced following pre-treatment with 1 mg/kg unlabeled MK-7246, by 66% in pancreas and 88% in spleen.…”

Section: Imaging Results—in Vivo Petmentioning

confidence: 99%

“…Biodistribution studies was performed in rat by small animal PET/MRI scanning for 11 C-MK-7246, to extrapolate the predicted radiation dose in humans [36••]. The excretion occurred mainly through the liver, biliary systems, and the intestines, as seen for both 11 C-MK-7246 in pig and for 11 C-AZ12204657 in both pig and NHP.…”

Section: Imaging Results—in Vivo Petmentioning

confidence: 99%

“…1c). Demethylated MK-7246 was also radiolabeled by addition of 11 C-CH 3 I, similar as for 11 C-AZ12204657 [36••]. Fevipriprant is also potentially an attractive imaging ligand, given its high nanomolar affinity and its relatively low lipophilicity (logP = 2.3) but is so far unexplored in the imaging setting [37].…”

Section: Development Of Gpr44 Imaging Ligandsmentioning

confidence: 99%

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GPR44 as a Target for Imaging Pancreatic Beta-Cell Mass

Eriksson

2019

Curr Diab Rep

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Purpose of Review Quantitative markers for beta-cell mass (BCM) in human pancreas are currently lacking. Medical imaging using positron emission tomography (PET) markers for beta-cell restricted targets may provide an accurate and non-invasive measurement of BCM, to assist diagnosis and treatment of metabolic disease. GPR44 was recently discovered as a putative marker for beta cells and this review summarizes the developments so far. Recent Findings Several small molecule binders targeting GPR44 have been radiolabeled for PET imaging and evaluated in vitro and in small and large animal models. 11 C-AZ12204657 and 11 C-MK-7246 displayed a dose-dependent and GPR44-mediated binding to beta cells both in vitro and in vivo, with negligible uptake in exocrine pancreas. Summary GPR44 represents an attractive target for visualization of BCM. Further progress in radioligand development including clinical testing is expected to clarify the role of GPR44 as a surrogate marker for BCM in humans.

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Section: Imaging Results—in Vitro Approachessupporting

confidence: 61%

Section: Imaging Results—in Vivo Petmentioning

confidence: 99%

Section: Imaging Results—in Vivo Petmentioning

confidence: 99%

Section: Development Of Gpr44 Imaging Ligandsmentioning

confidence: 99%

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GPR44 as a Target for Imaging Pancreatic Beta-Cell Mass

Eriksson

2019

Curr Diab Rep

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“…Furthermore, availability is limited to local production facilities as the short half-life restricts the ability to distribute these tracers. Several tracers developed as surrogate markers of beta-cell mass have utilized 11 C for use with PET including [ 11 C]DTBZ [ 49 ], [ 11 C]5-HTP [ 50 ], [ 11 C]AZ12204657 [ 134 ], and [ 11 C]MK7246 [ 135 ].…”

Section: Radiochemistry—appending Imaging Isotopes To Beta Cell Prmentioning

confidence: 99%

Beta Cell Imaging—From Pre-Clinical Validation to First in Man Testing

Demine

Schulte

Territo

et al. 2020

IJMS

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There are presently no reliable ways to quantify human pancreatic beta cell mass (BCM) in vivo, which prevents an accurate understanding of the progressive beta cell loss in diabetes or following islet transplantation. Furthermore, the lack of beta cell imaging hampers the evaluation of the impact of new drugs aiming to prevent beta cell loss or to restore BCM in diabetes. We presently discuss the potential value of BCM determination as a cornerstone for individualized therapies in diabetes, describe the presently available probes for human BCM evaluation, and discuss our approach for the discovery of novel beta cell biomarkers, based on the determination of specific splice variants present in human beta cells. This has already led to the identification of DPP6 and FXYD2ga as two promising targets for human BCM imaging, and is followed by a discussion of potential safety issues, the role for radiochemistry in the improvement of BCM imaging, and concludes with an overview of the different steps from pre-clinical validation to a first-in-man trial for novel tracers.

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