O-(2-18F-fluoroethyl)-l-tyrosine (18F-FET) uptake in insulinoma: first results from a xenograft mouse model and from human

Abstract

Introduction: Herein we have evaluated the uptake of O-(2-¹⁸F-fluoroethyl)-l-tyrosine (¹⁸F-FET) in insulinoma in comparison with those of 6-¹⁸F-fluoro-3,4-dihydroxy-l-phenylalanine (¹⁸F-FDOPA) providing first data from both murine xenograft model and one patient with proved endogenous hyperinsulinemic hypoglycemia.

Methods: Dynamic ¹⁸F-FET and carbidopa-assisted ¹⁸F-FDOPA PET were performed on tumor-bearing nude mice after subcutaneous injection of RIN-m5F murine beta cells and on a 30-year-old man with type-1 multiple endocrine neoplasia and hyperinsulinemic hypoglycemia defined by a positive fasting test.

Results: Seven and three nude mice bearing a RIN-m5F insulinoma xenograft were respectively studied by ¹⁸F-FET and ¹⁸F-FDOPA μPET. Insulinoma xenograft was detected in all the imaged animals. Xenograft was characterized by an early but moderate increase of ¹⁸F-FET uptake followed by a slight decline of uptake intensity during the 20 min dynamic acquisition. Tumoral radiotracer peak intensity and the highest tumor-to-background contrast were reached about 5 minutes after ¹⁸F-FET iv. injection (mean SUV: 1.21 ± 0.10). The biodistribution of ¹⁸F-FET and ¹⁸F-FDOPA and their dynamic tumoral uptake profile and intensity were similar. In the examined patient, ¹⁸F-FDOPA and ¹⁸F-FET PET/CT showed one concordant focal area of well-defined increased uptake in the pancreatic tail corresponding to 11 mm histologically proved insulinoma. The SUV_max tumor to liver ratio was 1.5, 1.1 for ¹⁸F-FDOPA, 1.1, 1 for ¹⁸F-FET at early (0-5 min post injection) and delayed (5-20 min post injection) PET/CT acquisition, respectively. Despite the relatively low tumoral uptake intensity, insulinoma was clearly identified due to the low background in the pancreas. At the contrary, no ¹⁸F-FDOPA or ¹⁸F-FET tumoral uptake was revealed on whole-body PET/CT images performed about 30 min after radiotracer administration. Note of worth, the dynamic uptake pattern of ¹⁸F-FET and ¹⁸F-FDOPA were similar between human insulinoma and mice xenograft tumor.

Conclusion: ¹⁸F-FET PET compared equally to ¹⁸F-FDOPA PET in a preclinical RIN-m5F murine model of insulinoma and in one patient with insulinoma-related hypoglycemia. However, in both cases, the tumoral uptake intensity was moderate and the tumor was only visible until 20 min after radiotracer injection. Hence, caution should be taken before asserting the translational relevance of our results in the clinical practices. However, the structural analogies between ¹⁸F-FET and ¹⁸F-FDOPA as well as the limited pancreatic uptake of ¹⁸F-FET in human, encourage evaluating ¹⁸F-FET as diagnostic radiotracer for insulinoma detection in further prospective studies involving large cohorts of patients.

Keywords: (18)F-FDOPA; (18)F-FET; Insulinoma; RIN-m5F; Small animal; microPET.