In Vitro Evaluation of [<sup>18</sup>F]Canagliflozin, a Potential PET Tracer for Imaging Tissue Distribution of the SGLT2 Inhibitor Canagliflozin in Type 2 Diabetes Patients In Vivo
October 22, 2020 | 10:00 AM - 12:00 PM
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In Vitro Evaluation of [18F]Canagliflozin, a Potential PET Tracer for Imaging Tissue Distribution of the SGLT2 Inhibitor Canagliflozin in Type 2 Diabetes Patients In Vivo
- Diabetic Kidney Disease: New Pathways and Therapies
October 22, 2020 | Location: On-Demand
Abstract Time: 10:00 AM - 12:00 PM
Category: Diabetic Kidney Disease
- 601 Diabetic Kidney Disease: Basic
- van der Hoek, Sjoukje, University Medical Center Groningen, Groningen, Netherlands
- Antunes, Inês F., University Medical Center Groningen, Groningen, Netherlands
- Van goor, Harry, University Medical Center Groningen, Groningen, Netherlands
- L Heerspink, Hiddo Jan, University Medical Center Groningen, Groningen, Netherlands
- Elsinga, Philip, University Medical Center Groningen, Groningen, Netherlands
- Stevens, Jasper, University Medical Center Groningen, Groningen, Netherlands
Sjoukje van der Hoek,
Inês F. Antunes,
Harry Van goor,
Hiddo Jan L Heerspink,
Sodium-glucose cotransporter 2 (SGLT2) inhibitors are guideline recommended for prevention of kidney and cardiovascular outcomes in patients with diabetic kidney disease. But not all patients benefit from these agents, possibly due to differences in SGLT2 inhibitor tissue distribution. Imaging studies can assist to quantify in vivo tissue drug distribution and SGLT2 density in patients in order to unravel the underlying determinants of this response variability. The objective of this study was firstly to synthesize [18F]canagliflozin ([18F]CANA) for human use, and secondly, to confirm its affinity for SGLT2.
[18F]CANA was synthesized by GMP compliant automated substitution of a boronic ester precursor with [18F]fluoride. Its in vitro binding with SGLT2 was tested by incubating human kidney slices with [18F]CANA alone or together with canagliflozin or glucose and analyzing them with autoradiography. [18F]CANA binding sites were compared with SGLT2 distribution using immunohistochemistry on consecutive slices.
[18F]CANA radiochemical yield was 2.0% ± 1.9% within 80 min, molar activity 5-20 GBq/µmol and radiochemical purity >99%. Autoradiography shows [18F]CANA binding in kidney slices with a significant reduction in binding in presence of canagliflozin and a clear trend in reduced binding in presence of glucose (Fig 1A and B). The pattern of [18F]CANA binding on autoradiography corresponds with the distribution of SGLT2 in the apical membrane of proximal tubules as shown with immunohistochemistry (Fig 1C).
We showed the successful automated synthesis of the SGLT2 inhibitor [18F]CANA and its specificity to the SGLT2. Given its unchanged structure compared to the marketed compound, canagliflozin tissue distribution and SGLT2 density can now be studied in vivo in human as determinants of between-patient response variability.
Figure 1. A and B: [18F]CANA binding in kidney sections with autoradiography. C: [18F]CANA binding using autoradiography compared with SGLT2 distribution using immunohistochemistry.
- Private Foundation Support