Effect of Carbidopa on ¹⁸F-FDOPA Uptake in Insulinoma: From Cell Culture to Small-Animal PET Imaging

Abstract

Patient premedication with carbidopa seems to improve the accuracy of 6-18 F-fluoro-3,4-dihydroxy-L-phenylalanine ( 18 F-FDOPA) PET for insulinoma diagnosis. However, the risk of PET false-negative results in the presence of carbidopa is a concern. Consequently, we aimed to evaluate the effect of carbidopa on 18 F-FDOPA uptake in insulinoma b-cells and an insulinoma xenograft model in mice. Methods: 18 F-FDOPA in vitro accumulation was assessed in the murine b-cell line RIN-m5F. In vivo small-animal PET experiments were performed on tumor-bearing nude mice after subcutaneous injection of RIN-m5F cells. Experiments were conducted with and without carbidopa pretreatment. Results: Incubation of RIN-m5F cells with 80 mM carbidopa did not significantly affect the cellular accumulation of 18 F-FDOPA. Tumor xenografts were clearly detectable by small-animal PET in all cases. Insulinoma xenografts in carbidopa-treated mice showed significantly higher 18 F-FDOPA uptake than those in nontreated mice. Regardless of carbidopa premedication, the xenografts were characterized by an early increase in 18 F-FDOPA uptake and then a progressive reduction over time. Conclusion: Carbidopa did not influence in vitro 18 F-FDOPA accumulation in RIN-m5F cells but improved insulinoma imaging in vivo. Our findings increase current knowledge about the 18 F-FDOPA uptake profile of RIN-m5F cells and a related xenograft model. To our knowledge, the present work represents the first preclinical research specifically focused on insulinomas, with potential translational implications.

Clinical Value of 18F-FDOPA PET/CT With Contrast Enhancement and Without Carbidopa Premedication in Patients with Insulinoma

“…In vivo small-animal PET experiments were performed on tumor-bearing nude mice after subcutaneous injection of RIN-m5F cells. With carbidopa premedication, there was no evidence of in vitro 18 F-FDOPA accumulation in RIN-m5F cells and in vivo imaging was improved (19). These findings suggest that carbidopa can be used to inhibit uptake in healthy pancreatic tissue without concern about masking lesions.…”

Carbidopa Capsules for Insulinoma Diagnostic: Compounding and Stability Study

“…[ 18 F]F-DOPA positron emission tomography (PET) has a broad range of diagnostic indications not only in neurology but also in oncology for detecting pheochromocytomas, paragangliomas, gliomas, and various neuroendocrine tumors including insulinomas. In adult patients, premedication with a single per os administration of 200 mg carbidopa improves the sensitivity of [ 18 F]F-DOPA PET for insulinoma diagnosis [1,2]. Carbidopa decreases physiological decarboxylation of [ 18 F]F-DOPA into [ 18 F] fluoro-dopamine, and also decreases its renal clearance [3].…”

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

“…18 F-FDOPA is internalized in cells via the sodium-independent L-amino acids transporter system (LAT), decarboxylated and stored into neurosecretory granules [14]. The positive impact of 18 F-FDOPA PET/CT for insulinoma diagnosis, particularly when combined with carbidopa premedication and early pancreatic images, has been recently demonstrated in preclinical studies based on insulinoma xenograft mouse model [15], and in clinical investigations involving adult patients with insulinoma-related hyperinsulinemic hypoglycemia [16,17]. However, although 18 F-FDOPA PET/CT does function, it is far from ideal.…”

“…To evaluate tumor functionality (i.e., insulin secretion), morning serum glycemia levels in the xenograft mice were assessed from blood samples collected from the tail vein of non-fasted mice using a commercial blood glucose monitoring system (Contour TS, Bayer). To reduce the occurrence of lethal hypoglycemia, water was replaced by a 20% glucose solution 15 days after the subcutaneous injection of RIN5-mF cells suspension [15]. PET data analyses were performed using the AMIDE software package (http://amide.sourceforge.net) as previously detailed [15].…”

“…To reduce the occurrence of lethal hypoglycemia, water was replaced by a 20% glucose solution 15 days after the subcutaneous injection of RIN5-mF cells suspension [15]. PET data analyses were performed using the AMIDE software package (http://amide.sourceforge.net) as previously detailed [15]. Briefly, a focal non-physiologic increase in radiotracer uptake in the area of Fig.…”