RT Journal Article
SR Electronic
T1 Development of a PET Tracer for OGA with Improved Kinetics in the Living Brain
JF Journal of Nuclear Medicine
JO J Nucl Med
FD Society of Nuclear Medicine
SP 1588
OP 1593
DO 10.2967/jnumed.122.265225
VO 64
IS 10
A1 Cook, Brendon E.
A1 Nag, Sangram
A1 Arakawa, Ryosuke
A1 Lin, Edward Yin-Shiang
A1 Stratman, Nancy
A1 Guckian, Kevin
A1 Hering, Heike
A1 Lulla, Mukesh
A1 Choi, Jinkuk
A1 Salinas, Cristian
A1 Genung, Nathan E.
A1 Morén, Anton Forsberg
A1 Bolin, Martin
A1 Boscutti, Giulia
A1 Plisson, Christophe
A1 Martarello, Laurent
A1 Halldin, Christer
A1 Kaliszczak, Maciej A.
YR 2023
UL http://jnm.snmjournals.org/content/64/10/1588.abstract
AB O-GlcNAcylation is thought to play a role in the development of tau pathology in Alzheimer’s disease because of its ability to modulate tau’s aggregation propensity. O-GlcNAcylation is regulated by 2 enzymes: O-GlcNAc transferase and O-GlcNAcase (OGA). Development of a PET tracer would therefore be an essential tool for developing therapeutic small-molecule inhibitors of OGA, enabling clinical testing of target engagement and dose selection. Methods: A collection of small-molecule compounds was screened for inhibitory activity and high-affinity binding to OGA, as well as favorable PET tracer attributes (multidrug resistance protein 1 efflux, central nervous system PET multiparameter optimization, etc.). Two lead compounds with high affinity and selectivity for OGA were selected for further profiling, including OGA binding to tissue homogenate using a radioligand competition binding assay. In vivo pharmacokinetics were established using a microdosing approach with unlabeled compounds in rats. In vivo imaging studies were performed in rodents and nonhuman primates (NHPs) with 11C-labeled compounds. Results: Two selected candidates, BIO-735 and BIO-578, displayed promising attributes in vitro. After radiolabeling with tritium, [3H]BIO-735 and [3H]BIO-578 binding in rodent brain homogenates demonstrated dissociation constants of 0.6 and 2.3 nM, respectively. Binding was inhibited, concentration-dependently, by homologous compounds and thiamet G, a well-characterized and structurally diverse OGA inhibitor. Imaging studies in rats and NHPs showed both tracers had high uptake in the brain and inhibition of binding to OGA in the presence of a nonradioactive compound. However, only BIO-578 demonstrated reversible binding kinetics within the time frame of a PET study with a 11C-labeled molecule to enable quantification using kinetic modeling. Specificity of tracer uptake was confirmed with a 10 mg/kg blocking dose of thiamet G. Conclusion: We describe the development and testing of 2 11C PET tracers targeting the protein OGA. The lead compound BIO-578 demonstrated high affinity and selectivity for OGA in rodent and human postmortem brain tissue, leading to its further testing in NHPs. NHP PET imaging studies showed that the tracer had excellent brain kinetics, with full inhibition of specific binding by thiamet G. These results suggest that the tracer [11C]BIO-578 is well suited for further characterization in humans.