In Vivo Visualization of β-Cells by Targeting of GPR44

Abstract

GPR44 expression has recently been described as highly β-cell selective in the human pancreas and constitutes a tentative surrogate imaging biomarker in diabetes. A radiolabeled small-molecule GPR44 antagonist, [C]AZ12204657, was evaluated for visualization of β-cells in pigs and nonhuman primates by positron emission tomography as well as in immunodeficient mice transplanted with human islets under the kidney capsule. In vitro autoradiography of human and animal pancreatic sections from subjects without and with diabetes, in combination with insulin staining, was performed to assess β-cell selectivity of the radiotracer. Proof of principle of in vivo targeting of human islets by [C]AZ12204657 was shown in the immunodeficient mouse transplantation model. Furthermore, [C]AZ12204657 bound by a GPR44-mediated mechanism in pancreatic sections from humans and pigs without diabetes, but not those with diabetes. In vivo [C]AZ12204657 bound specifically to GPR44 in pancreas and spleen and could be competed away dose-dependently in nondiabetic pigs and nonhuman primates. [C]AZ12204657 is a first-in-class surrogate imaging biomarker for pancreatic β-cells by targeting the protein GPR44.

Relative Pancreas Volume Is Reduced in First-Degree Relatives of Patients With Type 1 Diabetes

“…Surrogate biomarkers of b-cell function do exist but are relatively insensitive. Imaging studies that can directly assess b-cell mass are still not available for clinical use (43)(44)(45)(46). Our study supports the use of abdominal MRI to quantify RPV BMI in subjects at high risk for type 1 diabetes to understand intersubject heterogeneity, changes over time, and association with numbers of AAB.…”

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

“…Human pancreatic tissue was selected for the in vitro autoradiography assay, due to the potential of CRTH2 as a surrogate marker for BCM. [11] The focal [ 11 C]MK-7246 binding pattern was partially blockable (i.e. receptor mediated) and consistent with the heterogenous distribution of islets of Langerhans (as inferred from insulin staining), but also exhibited non-specific binding.…”

“…In the original route, nucleophilic ring-opening of aziridine 3 was followed by installation of the Nmethyl and an additional five synthetic steps to afford MK-7246. Due to the short half-life of 11 C, direct implementation of this approach to label MK-7246 was unfeasible and our strategy focused on allowing introduction of the N-methyl group as late as possible in the synthesis. Thus, the union of aziridine 3 and indole 4 was followed by concomitant protonation and TBS deprotection.…”

“…[ 11 C]MK-7246 is indeed more lipophilic than previously published CRTH2 radioligand [ 11 C]AZ12204657. [11] Longer washing steps may alleviate this technical issue specific to the assay but is not practically possible when using the short-lived carbon-11 radionuclide. Thus, further assessment of in vitro specificity may focus on homogenate binding of pure islet and exocrine fractions from pancreas islet isolations, as well as on model cell lines expressing CRTH2.…”

“…Due to the relative abundance of CRTH2 in β-cells and its absence from other endocrine cell-types and the acinar pancreas, CRTH2 has emerged as a novel target for imaging of BCM in diabetes research. [10,11] The possibility to study BCM in vivo using a noninvasive imaging technique such as Positron Emission Tomography (PET) would greatly contribute to the basic understanding of the processes surrounding diabetes and could also be pivotal in drug development, for example as a diagnostic tool for clinical trial inclusions and treatment follow-up.…”