The use of positron emitter–labeled compounds for somatostatin receptor imaging (SRI) has become attractive because of the prospect of improved spatial resolution, accelerated imaging procedures, and the ability to quantify tissue radioactivity concentrations. This paper provides results from first-in-humans use of ⁶⁴Cu-DOTATATE, an avidly binding somatostatin receptor ligand linked to a radioisotope with intermediate half-life and favorable positron energy (half-life, 12.7 h; maximum positron energy, 0.653 MeV). Methods: In a prospective setup, 14 patients with a history of neuroendocrine tumors underwent both PET/CT with ⁶⁴Cu-DOTATATE and SPECT/CT with our current routine imaging agent ¹¹¹In-diethylenetriaminepentaacetic acid–octreotide. After intravenous injection of 193–232 MBq of ⁶⁴Cu-DOTATATE, whole-body PET scans were acquired at 1 h (n = 14), 3 h (n = 12), and 24 h (n = 5) after administration. Tissue radioactivity concentrations for normal organs and lesions were quantified, and standardized uptake values were calculated for the early (1 h) and delayed (3 h) scans. Using the data for 5 patients, we assessed the radiation dose with OLINDA/EXM software. Furthermore, the clinical performance of ⁶⁴Cu-DOTATATE with respect to lesion detection was compared with conventional SRI. Results: SRI with ⁶⁴Cu-DOTATATE produced images of excellent quality and high spatial resolution. Images were characterized by high and stable tumor-to-background ratios over an imaging time window of at least 3 h. Compared with conventional scintigraphy, ⁶⁴Cu-DOTATATE PET identified additional lesions in 6 of 14 patients (43%). In 5 patients, lesions were localized in organs and organ systems not previously known as metastatic sites, including the early-stage detection of a secondary neuroendocrine tumor in a patient with a known mutation in the multiple endocrine neoplasia type I gene. All major additional findings seen only on PET could be confirmed on the basis of a clinical follow-up interval of 18 mo. Calculated radiation dose estimates yielded an effective dose of 6.3 mSv for an injected activity of 200 MBq of ⁶⁴Cu-DOTATATE, with the liver being the organ with the highest absorbed radiation dose (0.16 mGy/MBq). Conclusion: This first-in-humans study supports the clinical use of ⁶⁴Cu-DOTATATE for SRI with excellent imaging quality, reduced radiation burden, and increased lesion detection rate when compared with ¹¹¹In-diethylenetriaminepentaacetic acid–octreotide.

Neuroendocrine tumors (NETs) can be visualized using radiolabeled somatostatin analogs. We have previously shown the clinical potential of ⁶⁴Cu-DOTATATE in a small first-in-human feasibility study. The aim of the present study was, in a larger prospective design, to compare on a head-to-head basis the performance of ⁶⁴Cu-DOTATATE and ¹¹¹In-DTPA-octreotide (¹¹¹In-DTPA-OC) as basis for implementing ⁶⁴Cu-DOTATATE as a routine. Methods: We prospectively enrolled 112 patients with pathologically confirmed NETs of gastro-entero-pancreatic or pulmonary origin. All patients underwent both PET/CT with ⁶⁴Cu-DOTATATE and SPECT/CT with ¹¹¹In-DTPA-OC within 60 days. PET scans were acquired 1 hour post-injection of 202 MBq (range 183 – 232 MBq) ⁶⁴Cu-DOTATATE following a diagnostic contrast-enhanced CT scan. Patients were followed for 42-60 months for evaluation of discrepant imaging findings. McNemar’s test was used to compare the diagnostic performance. Results: 87 patients were congruently PET and SPECT positive. No SPECT positive cases were PET negative, while 10 false-negative SPECT cases were identified using PET. Diagnostic sensitivity and accuracy of ⁶⁴Cu-DOTATATE (97% for both) were significantly better than that of ¹¹¹In-DTPA-OC (87% and 88% respectively, P = 0.017). In 84 patients (75%) ⁶⁴Cu-DOTATATE identified more lesions than ¹¹¹In-DTPA-OC and always at least as many. In total, twice as many lesions were detected using ⁶⁴Cu-DOTATATE compared to ¹¹¹In-DTPA-OC. Moreover, in 40 of 112 cases (36%) lesions were detected by ⁶⁴Cu-DOTATATE in organs not identified as disease-involved by ¹¹¹In-DTPA-OC. Conclusion: With these results, we demonstrate that ⁶⁴Cu-DOTATATE is far superior to ¹¹¹In-DTPA-OC in diagnostic performance in NET patients. Therefore, we do not hesitate to recommend implementation of ⁶⁴Cu-DOTATATE as replacement for ¹¹¹In-DTPA-OC.

Background: The somatostatin receptor subtype 2 (SSTR2) is expressed on macrophages, an abundant cell type in the atherosclerotic plaque. Visualization of SSTR2, for oncological purposes, is frequently made using the 1,4,7,10-tetraazacyclodecane-1,4,7,10-tetraaceticacid (DOTA)-derived somatostatin analogues DOTA-Tyr3-octreotide (DOTATOC) or DOTA-Tyr3-octreotate (DOTATATE) for positron emission tomography (PET). We aimed to compare the uptake of the PET-tracers ⁶⁸Ga-DOTATOC and ⁶⁴Cu-DOTATATE in large arteries, in assessment of atherosclerosis by non-invasive imaging technique, combining PET and CT. Further, the correlation of uptake and cardiovascular risk factors was investigated. Methods: Sixty consecutive patients with neuroendocrine tumors underwent both ⁶⁸Ga-DOTATOC and ⁶⁴Cu-DOTATATE PET/CT-scans, in random order. For each scan, the maximum and mean standardized uptake values (SUV) were calculated in five arterial segments, respectively. In addition, blood-pool corrected target-to-background ratio (TBR) was calculated. Uptake of the tracers was correlated with cardiovascular risk factors collected from medical records. Results: We found detectable uptake of both tracers in all arterial segments studied. Uptake of ⁶⁴Cu-DOTATATE was significantly higher than ⁶⁸Ga-DOTATOC in the vascular regions both when calculated as maximum and mean uptake. There was a significant association between Framingham risk score and the overall maximum uptake of ⁶⁴Cu-DOTATATE using SUV (r=0.4; P = 0.004) as well as TBR (r=0.3; P = 0.04), while no association was found with ⁶⁸Ga-DOTATOC. The association of Framingham risk score and maximum SUV of ⁶⁴Cu-DOTATATE was found driven by BMI, smoking and diabetes (p<0.001, P = 0.032, P = 0.025, respectively). Conclusion: In a series of oncologic patients, vascular uptake of ⁶⁸Ga-DOTATOC and ⁶⁴Cu-DOTATATE was found, with highest uptake of the latter. Uptake of ⁶⁴Cu-DOTATATE, but not of ⁶⁸Ga-DOTATOC, was correlated with cardiovascular risk factors, suggesting a potential role for ⁶⁴Cu-DOTATATE in assessment of atherosclerosis.