Radio-manganese PET imaging of pancreatic beta cells

Objectives Noninvasive assessment of pancreatic beta cell mass and function is of great interest for the diagnosis and treatment of diabetes mellitus. Current strategies lack sufficient sensitivity and specificity for the detection of native or transplanted beta cells. The mechanism of Ca²⁺ influx by beta cells, which is inextricably associated with beta cell function, allows for the specific uptake of manganese. Our goal is to employ ⁵²Mn (T_1/2: 5.5 d) as radiotracer for positron emission tomography (PET) imaging of pancreatic beta cells in mice.

Methods ⁵²Mn was produced in a GE PETtrace cyclotron via irradiation of natural chromium targets, separated using ethanolic anion exchange chromatography, and radioactive fractions eluted in 0.01 M NaAc (pH 6.0). To assess pancreatic uptake, normal and fasted ICR mice were administered an intravenous bolus of 1.5 MBq of ⁵²Mn. One-hour dynamic, then sequential static PET scans were acquired over a period of 96 h to characterize the early pharmacokinetics of ⁵²Mn and its long-term in vivo biodistribution. Regions of interest (ROIs) were drawn over the organs with prominent uptake including the heart, liver, kidneys, pancreas, and thyroid, and the results reported as percent injected dose per gram of tissue (%ID/g). To demonstrate the correlation between pancreatic ⁵²Mn uptake and beta cell function, mice were administered an insulin release stimulator (glibenclamide; 5mg/kg) or an insulin release blocker (diazoxide; 20 mg/kg) intraperitoneally, 10 min before injection of ⁵²Mn. Static PET scans were acquired 1 h post injection (p.i.) of the radiometal and the pancreatic uptake compared between groups. To validate the quantitative PET data, ex vivo biodistribution studies were performed after the final imaging time point.

Results Dynamic PET imaging revealed fast clearance of ⁵²Mn from circulation and a prominent accumulation in pancreas, kidneys, heart muscle, thyroid, and liver. Following rapid bolus injection, ⁵²Mn showed a 10 s circulation half-life, which resulted in the rapid stabilization of its uptake in the aforementioned organs, from which very little activity was excreted at day 4 after administration of the radiometal. In mice fasted for 6-12 h, ⁵²Mn uptake in the pancreas reached 19.3 ± 3.7 %ID/g (n = 4), 1h p.i.. A noticeable increase in pancreatic uptake to 24.9 ± 1.8 %ID/g (n = 4) was observed when insulin release was stimulated by co-injection of glucose and glibenclamide. On the other hand, when insulin release was impaired by the administration of diaxozide, mice experienced a significantly lower pancreatic uptake of ⁵²Mn (14.0 ± 2.7 %ID/g; n = 3) compared to both stimulated and normal pancreata. ⁵²Mn uptake in non-target organs was similar across all groups. Excellent agreement was observed between ex vivo and PET biodistribution data, which demonstrated the ability of PET to detect and accurately quantify ⁵²Mn tissue distribution.

Conclusions To date, the use of radioactive manganese for PET imaging of pancreatic beta cells has not been reported. Herein, we demonstrated that ⁵²Mn PET imaging of the pancreas is promising for the study of beta cell functional mass. Compared to manganese-based MRI methods, ⁵²Mn-PET provides improved sensitivity, dynamic range, clearance, and reduced toxicity for beta cell imaging. PET studies with ⁵²Mn or ⁵¹Mn, whose shorter physical half-live (T_1/2: 46 min) better matches the fast kinetics of Mn in vivo, are currently undergoing to evaluate the evolution of beta cell functional mass in a mouse model of type I diabetes mellitus.

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