64Cu-SARTATE PET Imaging of Patients with Neuroendocrine Tumors Demonstrates High Tumor Uptake and Retention, Potentially Allowing Prospective Dosimetry for Peptide Receptor Radionuclide Therapy

Abstract

Imaging of somatostatin receptor expression is an established technique for staging of neuroendocrine neoplasia and determining the suitability of patients for peptide receptor radionuclide therapy. PET/CT using ⁶⁸Ga-labeled somatostatin analogs is superior to earlier agents, but the rapid physical decay of the radionuclide poses logistic and regulatory challenges. ⁶⁴Cu has attractive physical characteristics for imaging and provides a diagnostic partner for the therapeutic radionuclide ⁶⁷Cu. Based on promising preclinical studies, we have performed a first-time-in-humans trial of ⁶⁴Cu-MeCOSar-Tyr³-octreotate (⁶⁴Cu-SARTATE) to assess its safety and ability to localize disease at early and late imaging time-points. Methods: In a prospective trial, 10 patients with known neuroendocrine neoplasia and positive for uptake on ⁶⁸Ga-DOTA-octreotate (⁶⁸Ga-DOTATATE) PET/CT underwent serial PET/CT imaging at 30 min, 1 h, 4 h, and 24 h after injection of ⁶⁴Cu-SARTATE. Adverse reactions were recorded, and laboratory testing was performed during infusion and at 1 and 7 d after imaging. Images were analyzed for lesion and normal-organ uptake and clearance to assess lesion contrast and perform dosimetry estimates. Results:⁶⁴Cu-SARTATE was well tolerated during infusion and throughout the study, with 3 patients experiencing mild infusion-related events. High lesion uptake and retention were observed at all imaging time-points. There was progressive hepatic clearance over time, providing the highest lesion-to-liver contrast at 24 h. Image quality remained high at this time. Comparison of ⁶⁴Cu-SARTATE PET/CT obtained at 4 h to ⁶⁸Ga-DOTATATE PET/CT obtained at 1 h indicated comparable or superior lesion detection in all patients, especially in the liver. As expected, the highest early physiologic organ uptake was in the kidneys, liver, and spleen. Conclusion:⁶⁴Cu-SARTATE is safe and has excellent imaging characteristics. High late-retention in tumor and clearance from the liver suggest suitability for diagnostic studies and for prospective dosimetry for ⁶⁷Cu-SARTATE peptide receptor radionuclide therapy, and the half-life of ⁶⁴Cu would also facilitate good-manufacturing-practice production and distribution to sites without access to ⁶⁸Ga.

Keywords: copper-64; neuroendocrine tumor; peptide receptor radionuclide therapy; positron emission tomography; radiopharmaceuticals; theranostics.

FIGURE 1.

Study flow chart.

FIGURE 2.

Comparison of tracers. Maximum-intensity projections obtained at 1 h for ⁶⁸Ga-DOTATATE (GaTate) are compared with those obtained at 30 min, 1 h, 4 h, and 24 h for ⁶⁴Cu-SARTATE. Although ⁶⁴Cu-SARTATE images were deemed comparable at 1 h in 9 of 10 patients (patient 6 was the exception), all were considered equivalent or superior to ⁶⁸Ga-DOTATATE at both 4 h and 24 h.

FIGURE 3.

Superior lesion detection at 4 h. High lesion contrast on ⁶⁴Cu-SARTATE images at 4 h (right) better defines regional nodal disease than ⁶⁸Ga-DOTATATE images at 1 h (left) in patient with large pancreatic primary tumor but slightly greater small-bowel activity, indicating some hepatobiliary excretion.