Positron emission tomography to assess drug occupancy at peripheral and central incretin receptors.
Khalil. Amina A; Velikyan. Irina I; Xiong. Mengfei M; Bossart. Martin M; Wagner. Michael M; Eriksson. Olof O
Key Findings
- PET tracers [68Ga]Ga-DO3A-Exendin-4 and [68Ga]S02-GIP-T4 specifically bind to GLP‑1R and GIPR, confirming they can measure receptor occupancy.
- SAR441255 achieved >70% GLP‑1R occupancy in the pancreas and >60% in brain regions linked to appetite, in a dose‑dependent way.
- Tirzepatide showed lower GLP‑1R occupancy in both pancreas and brain compared with SAR441255, indicating weaker central receptor engagement.
- SAR441255 also reduced GIP‑tracer uptake in the pancreas by about 23%, showing it can engage the GIP receptor as well.
Practical Outcomes
- For biohackers using tirzepatide, expect most of its effects to come from peripheral (pancreas, gut) actions rather than direct brain modulation. If you aim for appetite‑suppressing benefits that rely on central GLP‑1R activation, higher doses or different compounds may be needed. The study provides a mechanistic check but does not yet translate into specific dosing guidelines for humans.
Summary
A PET scan study in pigs showed that tirzepatide does bind to the gut hormone receptor GLP‑1R in the pancreas, but it reaches the brain much less than a newer triple‑agonist drug (SAR441255). The triple‑agonist also hits the GIP receptor in the pancreas. This suggests tirzepatide’s main action is outside the brain, while stronger brain engagement may need different compounds or higher doses.
Abstract
Incretin mimetics, especially dual/triple agonists, are effective for type 2 diabetes and obesity, though mechanisms remain unclear. This study applied PET using [<sup>68</sup>Ga]Ga-DO3A-Exendin-4 and [<sup>68</sup>Ga]S02-GIP-T4 to assess GLP-1R and GIPR occupancy of SAR441255 (a GLP-1R, GIPR, and GCGR agonist) and tirzepatide in pig pancreas and CNS. In vitro binding assays on frozen HEK293 cell sections overexpressing human GLP-1R, GIPR, or GCGR assessed [<sup>68</sup>Ga]Ga-DO3A-Exendin-4 specificity and competition with tirzepatide and SAR441255, and [<sup>68</sup>Ga]S02-GIP-T4 with SAR441255. In vivo, the GLP-1R occupancy by SAR441255 and tirzepatide, and GIPR occupancy by SAR441255, was evaluated in healthy pigs using PET/CT initiated at tracer injection. A subcutaneous dose of the study drug was then administered, and a second scan was performed 2.5 h later. Occupancy was determined by comparing pancreatic and CNS tracer SUV before and after dosing. Two animals were used to compare the tracers directly. [<sup>68</sup>Ga]Ga-DO3A-Exendin-4 and [<sup>68</sup>Ga]S02-GIP-T4 showed high specificity for GLP-1R and GIPR, respectively, and competed with the study drugs in vitro. In vivo, SAR441255 induced dose-dependent GLP-1R occupancy (>70%) in pancreas and pituitary and (>60%) in CNS, while tirzepatide showed lower occupancy. SAR441255 also reduced pancreatic [<sup>68</sup>Ga]S02-GIP-T4 uptake by 23 ± 8.5%, indicating GIPR engagement. PET imaging in pigs demonstrated in vivo GLP-1R engagement by SAR441255 and tirzepatide, and GIPR engagement by SAR441255 in the pancreas. SAR441255 exhibited dose-dependent GLP-1R occupancy in the pancreas and brain regions linked to appetite regulation. The study was funded by Uppsala Diabetes Center, Diabetesfonden, ExoDiab, Diabetes Wellness Sweden, Barndiabetesfonden, Science for Life Laboratory, and the Swedish Research Council.
Study Information
pubmed
2025
2025-11-21T00:00:00.000Z
10.1016/j.ebiom.2025.106033
41