PET Imaging of Pancreatic Dopamine D2 and D3 Receptor Density with 11C-(+)-PHNO in Type 1 Diabetes

Type 1 diabetes mellitus (T1DM) has traditionally been characterized by a complete destruction of beta-cell mass (BCM); however, there is growing evidence of possible residual BCM present in T1DM. Given the absence of in vivo tools to measure BCM, routine clinical measures of beta-cell function (e.g., C-peptide release) may not reflect BCM. We previously demonstrated the potential utility of PET imaging with the dopamine D-2 and D-3 receptor agonist 3,4,4a,5,6,10b-hexahydro-2H-naphtho[1,2-b][1,4]oxazin-9-ol (C-11-(1)-PHNO) to differentiate between healthy control (HC) and T1DM individuals. Methods: Sixteen individuals participated (10 men, 6 women; 9 HCs, 7 T1DMs). The average duration of diabetes was 18 +/- 6 y (range, 14-30 y). Individuals underwent PET/CT scanning with a 120-min dynamic PET scan centered on the pancreas. One- and 2-tissue-compartment models were used to estimate pancreas and spleen distribution volume. Reference region approaches (spleen as reference) were also investigated. Quantitative PET measures were correlated with clinical outcome measures. Immunohistochemistry was performed to examine colocalization of dopamine receptors with endocrine hormones in HC and T1DM pancreatic tissue. Results: C-peptide release was not detectable in any T1DM individuals, whereas proinsulin was detectable in 3 of 5 T1DM individuals. Pancreas SUV ratio minus 1 (SUVR-1) (20-30 min; spleen as reference region) demonstrated a statistically significant reduction (-36.2%) in radioligand binding (HCs, 5.6; T1DMs, 3.6; P = 0.03). Age at diagnosis correlated significantly with pancreas SUVR-1 (20-30 min) (R-2 = 0.67, P = 0.025). Duration of diabetes did not significantly correlate with pancreas SUVR-1 (20-30 min) (R-2 = 0.36, P = 0.16). Mean acute C-peptide response to arginine at maximal glycemic potentiation did not significantly correlate with SUVR- 1 (20-30 min) (R-2 = 0.57, P = 0.05), nor did mean baseline proinsulin (R-2 = 0.45, P = 0.10). Immunohistochemistry demonstrated colocalization of dopamine D-3 receptor and dopamine D-2 receptor in HCs. No colocalization of the dopamine D-3 receptor or dopamine D-2 receptor was seen with somatostatin, glucagon, or polypeptide Y. In a separate T1DM individual, no immunostaining was seen with dopamine D-3 receptor, dopamine D-2 receptor, or insulin antibodies, suggesting that loss of endocrine dopamine D-3 receptor and dopamine D-2 receptor expression accompanies loss of beta-cell functional insulin secretory capacity. Conclusion: Thirty-minute scan durations and SUVR-1 provide quantitative outcome measures for C-11-(1)-PHNO, a dopamine D-3 receptor-preferring agonist PET radioligand, to differentiate BCM in T1DM and HCs.