In Vivo Biodistribution of No-Carrier-Added 6-18F-Fluoro-3,4-Dihydroxy-l-Phenylalanine (18F-DOPA), Produced by a New Nucleophilic Substitution Approach, Compared with Carrier-Added 18F-DOPA, Prepared by Conventional Electrophilic Substitution

Kuik, Willem Jan; Kema, Ido P.; Brouwers, Adrienne H.; Zijlma, Rolf; Neumann, Kiel D.; Dierckx, Rudi; DiMagno, Stephen G.; Elsinga, Philip H.

doi:10.2967/jnumed.114.145730

Cited by 63 publications

(36 citation statements)

References 29 publications

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“…The biodistribution data showed normal organ uptake similar to that seen with other amino acid analogs [16][17][18][19][20][21][22]. In these reports, relatively high uptake is seen in the pancreas, and consistent with this, 5-[…”

Section: In This Work 5-[supporting

confidence: 74%

Synthesis and Preliminary Evaluation of 5-[18F]fluoroleucine

Chin

McDougald

Weitzel

et al. 2017

CRP

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Background: Amino acid transporters, such as LAT1, are overexpressed in aggressive prostate and breast carcinomas, directly influencing pathways of growth and proliferation.Objective: The purpose of this study was to synthesize and characterize a novel 18 F labeled leucine analog, 5-[18 F]fluoroleucine, as a potential imaging agent for aggressive tumors which may not be amenable to imaging by FDG PET.Methods: 5-fluoroleucine was synthesized and characterized, and its 18 F-labeled analog was synthesized from a mesylate precursor. First, breast cancer cell line assays were performed to evaluate uptake of 3 H-or 14 C-labeled L-leucine and other essential amino acids. Both L-leucine and 5-[ 18 F]fluoroleucine were tested for uptake and accumulation over time, and for uptake via LAT1. Biodistribution studies were performed to estimate radiation dosimetry for human studies. Small animal PET / CT studies of a breast cancer were performed to evaluate in vivo 5-[18 F]fluoroleucine tumor uptake. Results: Breast cancer cell lines showed increasing high net accumulation of L-[14 C]leucine. Both L-leucine and 5-[18 F]fluoroleucine showed increasing uptake over time in in vitro tumor cell assays, and uptake was also shown to occur via LAT1. The biodistribution study of 5-[18 F]fluoroleucine showed rapid renal excretion, no significant in vivo metabolism, and acceptable dosimetry for use in humans. In vivo small animal PET / CT imaging of a breast cancer xenograft showed uptake of 5-[ 18 F]fluoroleucine in the tumor, which progressively increased over time. Conclusion: 5-[18 F]fluoroleucine is a leucine analog which may be useful in identifying tumors with high or upregulated expression of amino acid transporters, providing additional information that may not be provided by FDG PET.

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Section: In This Work 5-[supporting

confidence: 74%

Synthesis and Preliminary Evaluation of 5-[18F]fluoroleucine

Chin

McDougald

Weitzel

et al. 2017

CRP

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“…Once internalized via the sodium-independent system L, 18 F-FDOPA is decarboxylated to 18 F-dopamine, transported, and stored in cellular neurosecretory granules. A recently proposed radiosynthesis process based on nucleophilic substitution would allow the production of high-specific-activity 18 F-FDOPA (42). 18 F-FDOPA PET/CT sensitivity is low (25%) in high-grade GEP NETs and NETs arising from the foregut and hindgut (43).…”

Section: F-fluorodihydroxyphenylalanine ( F-fdopa)mentioning

confidence: 99%

Molecular Imaging of Gastroenteropancreatic Neuroendocrine Tumors: Current Status and Future Directions

et al. 2016

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Learning Objectives: On successful completion of this activity, participants should be able to (1) summarize the main clinical features of gastroenteropancreatic neuroendocrine tumors; (2) describe the specific mechanisms of uptake of radiotracers and identify the relation of imaging phenotype with site of origin and tumor grade; and (3) recommend the best imaging modalities across the different tumor subtypes for imaging and for selecting candidates for peptide receptor radionuclide therapy.

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“…The positive impact of carbidopa premedication has been demonstrated in both in vitro and in vivo studies with cell lines of human pancreatic NETs (BON cells) and a related tumor xenograft animal model (11,12). To the best of our knowledge, no preclinical data concerning the influence of carbidopa on 18 F-FDOPA uptake in insulinomas are available.…”

mentioning

confidence: 99%

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

Détour¹,

Aimar²,

Boisson³

et al. 2016

J Nucl Med

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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.

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In Vivo Biodistribution of No-Carrier-Added 6-¹⁸F-Fluoro-3,4-Dihydroxy-l-Phenylalanine (¹⁸F-DOPA), Produced by a New Nucleophilic Substitution Approach, Compared with Carrier-Added ¹⁸F-DOPA, Prepared by Conventional Electrophilic Substitution

Cited by 63 publications

References 29 publications

Synthesis and Preliminary Evaluation of 5-[18F]fluoroleucine

Synthesis and Preliminary Evaluation of 5-[18F]fluoroleucine

Molecular Imaging of Gastroenteropancreatic Neuroendocrine Tumors: Current Status and Future Directions

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

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In Vivo Biodistribution of No-Carrier-Added 6-18F-Fluoro-3,4-Dihydroxy-l-Phenylalanine (18F-DOPA), Produced by a New Nucleophilic Substitution Approach, Compared with Carrier-Added 18F-DOPA, Prepared by Conventional Electrophilic Substitution

Cited by 63 publications

References 29 publications

Synthesis and Preliminary Evaluation of 5-[18F]fluoroleucine

Synthesis and Preliminary Evaluation of 5-[18F]fluoroleucine

Molecular Imaging of Gastroenteropancreatic Neuroendocrine Tumors: Current Status and Future Directions

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

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Product

Resources

About

In Vivo Biodistribution of No-Carrier-Added 6-¹⁸F-Fluoro-3,4-Dihydroxy-l-Phenylalanine (¹⁸F-DOPA), Produced by a New Nucleophilic Substitution Approach, Compared with Carrier-Added ¹⁸F-DOPA, Prepared by Conventional Electrophilic Substitution

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