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

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

Research output: Contribution to journalArticle

31 Citations (Scopus)

Abstract

A novel synthetic approach to 6-18F-fluoro-3, 4-dihydroxy-L-phenylalanine (18F-DOPA), involving the nucleophilic substitution of a diaryliodonium salt precursor with non-carrier-added 18F-fluoride, yielded a product with a specific activity that was 3 orders of magnitude higher than the product of the conventional synthesis method involving an electrophilic substitution of a trialkylstannane precursor with 18F2. We performed a direct comparison of high- and lowspecific- activity 18F-DOPA in a neuroendocrine tumor model to determine whether this difference in specific activity has implications for the biologic behavior and imaging properties of 18F-DOPA.

Methods: 18F-DOPA was produced via the novel synthesis method, yielding 18F-DOPA-H with a high specific activity (35, 050 ± 4, 000 GBq/mmol). This product was compared in several experiments with conventional 18F-DOPA-L with a low specific activity (11 ± 2 GBq/mmol). In vitro accumulation experiments with the human pancreatic neuroendocrine tumor cell line BON-1 were performed at both 0°C and 37°C and at 37°C in the presence of pharmacologic inhibitors of proteins involved in the uptake mechanism of 18FDOPA. Small-animal PET experiments were performed in athymic nude mice bearing a BON-1 tumor xenograft.

Results: At 37°C, the uptake of both 18F-DOPA-H and 18F-DOPA-L did not differ significantly during a 60-min accumulation experiment in BON-1 cells. At 0°C, the uptake of 18F-DOPA-L was significantly decreased, whereas the lower temperature did not alter the uptake of 18FDOPA- H. The pharmacologic inhibitors carbidopa and tetrabenazine also revealed differential effects between the 2 types of 18FDOPA in the 60-min accumulation experiment. The small-animal PET experiments did not show any significant differences in distribution and metabolism of 18F-DOPA-H and 18F-DOPA-L in carbidopapretreated mice.

Conclusion: The advantages of the novel synthesis of 18F-DOPA, which relies on nucleophilic fluorination of a diaryliodonium salt precursor, lie in the simplicity of the synthesis method, compared with the conventional, electrophilic approach and in the reduced mass of administered, pharmacologically active 19F-DOPA. 18F-DOPA-H demonstrated comparable imaging properties in an in vivo model for neuroendocrine tumors, despite the fact that the injected mass of material was 3 orders of magnitude less than 18F-DOPA-L.

Original languageEnglish (US)
Pages (from-to)106-112
Number of pages7
JournalJournal of Nuclear Medicine
Volume56
Issue number1
DOIs
StatePublished - Jan 1 2015

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Phenylalanine
Neuroendocrine Tumors
Nude Mice
Salts
Tetrabenazine
Carbidopa
Neuroendocrine Cells
Halogenation
Tumor Cell Line
Fluorides
Heterografts

Keywords

  • Diaryliodonium salt
  • F
  • F-DOPA
  • Neuroendocrine tumors
  • PET

ASJC Scopus subject areas

  • Radiology Nuclear Medicine and imaging

Cite this

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 A.J.O.; DiMagno, Stephen G.; Elsinga, Philip H.

In: Journal of Nuclear Medicine, Vol. 56, No. 1, 01.01.2015, p. 106-112.

Research output: Contribution to journalArticle

Kuik, Willem Jan ; Kema, Ido P. ; Brouwers, Adrienne H. ; Zijlma, Rolf ; Neumann, Kiel D. ; Dierckx, Rudi A.J.O. ; DiMagno, Stephen G. ; Elsinga, Philip H. / 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. In: Journal of Nuclear Medicine. 2015 ; Vol. 56, No. 1. pp. 106-112.
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abstract = "A novel synthetic approach to 6-18F-fluoro-3, 4-dihydroxy-L-phenylalanine (18F-DOPA), involving the nucleophilic substitution of a diaryliodonium salt precursor with non-carrier-added 18F-fluoride, yielded a product with a specific activity that was 3 orders of magnitude higher than the product of the conventional synthesis method involving an electrophilic substitution of a trialkylstannane precursor with 18F2. We performed a direct comparison of high- and lowspecific- activity 18F-DOPA in a neuroendocrine tumor model to determine whether this difference in specific activity has implications for the biologic behavior and imaging properties of 18F-DOPA.Methods: 18F-DOPA was produced via the novel synthesis method, yielding 18F-DOPA-H with a high specific activity (35, 050 ± 4, 000 GBq/mmol). This product was compared in several experiments with conventional 18F-DOPA-L with a low specific activity (11 ± 2 GBq/mmol). In vitro accumulation experiments with the human pancreatic neuroendocrine tumor cell line BON-1 were performed at both 0°C and 37°C and at 37°C in the presence of pharmacologic inhibitors of proteins involved in the uptake mechanism of 18FDOPA. Small-animal PET experiments were performed in athymic nude mice bearing a BON-1 tumor xenograft.Results: At 37°C, the uptake of both 18F-DOPA-H and 18F-DOPA-L did not differ significantly during a 60-min accumulation experiment in BON-1 cells. At 0°C, the uptake of 18F-DOPA-L was significantly decreased, whereas the lower temperature did not alter the uptake of 18FDOPA- H. The pharmacologic inhibitors carbidopa and tetrabenazine also revealed differential effects between the 2 types of 18FDOPA in the 60-min accumulation experiment. The small-animal PET experiments did not show any significant differences in distribution and metabolism of 18F-DOPA-H and 18F-DOPA-L in carbidopapretreated mice.Conclusion: The advantages of the novel synthesis of 18F-DOPA, which relies on nucleophilic fluorination of a diaryliodonium salt precursor, lie in the simplicity of the synthesis method, compared with the conventional, electrophilic approach and in the reduced mass of administered, pharmacologically active 19F-DOPA. 18F-DOPA-H demonstrated comparable imaging properties in an in vivo model for neuroendocrine tumors, despite the fact that the injected mass of material was 3 orders of magnitude less than 18F-DOPA-L.",
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T1 - 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

AU - Kuik, Willem Jan

AU - Kema, Ido P.

AU - Brouwers, Adrienne H.

AU - Zijlma, Rolf

AU - Neumann, Kiel D.

AU - Dierckx, Rudi A.J.O.

AU - DiMagno, Stephen G.

AU - Elsinga, Philip H.

PY - 2015/1/1

Y1 - 2015/1/1

N2 - A novel synthetic approach to 6-18F-fluoro-3, 4-dihydroxy-L-phenylalanine (18F-DOPA), involving the nucleophilic substitution of a diaryliodonium salt precursor with non-carrier-added 18F-fluoride, yielded a product with a specific activity that was 3 orders of magnitude higher than the product of the conventional synthesis method involving an electrophilic substitution of a trialkylstannane precursor with 18F2. We performed a direct comparison of high- and lowspecific- activity 18F-DOPA in a neuroendocrine tumor model to determine whether this difference in specific activity has implications for the biologic behavior and imaging properties of 18F-DOPA.Methods: 18F-DOPA was produced via the novel synthesis method, yielding 18F-DOPA-H with a high specific activity (35, 050 ± 4, 000 GBq/mmol). This product was compared in several experiments with conventional 18F-DOPA-L with a low specific activity (11 ± 2 GBq/mmol). In vitro accumulation experiments with the human pancreatic neuroendocrine tumor cell line BON-1 were performed at both 0°C and 37°C and at 37°C in the presence of pharmacologic inhibitors of proteins involved in the uptake mechanism of 18FDOPA. Small-animal PET experiments were performed in athymic nude mice bearing a BON-1 tumor xenograft.Results: At 37°C, the uptake of both 18F-DOPA-H and 18F-DOPA-L did not differ significantly during a 60-min accumulation experiment in BON-1 cells. At 0°C, the uptake of 18F-DOPA-L was significantly decreased, whereas the lower temperature did not alter the uptake of 18FDOPA- H. The pharmacologic inhibitors carbidopa and tetrabenazine also revealed differential effects between the 2 types of 18FDOPA in the 60-min accumulation experiment. The small-animal PET experiments did not show any significant differences in distribution and metabolism of 18F-DOPA-H and 18F-DOPA-L in carbidopapretreated mice.Conclusion: The advantages of the novel synthesis of 18F-DOPA, which relies on nucleophilic fluorination of a diaryliodonium salt precursor, lie in the simplicity of the synthesis method, compared with the conventional, electrophilic approach and in the reduced mass of administered, pharmacologically active 19F-DOPA. 18F-DOPA-H demonstrated comparable imaging properties in an in vivo model for neuroendocrine tumors, despite the fact that the injected mass of material was 3 orders of magnitude less than 18F-DOPA-L.

AB - A novel synthetic approach to 6-18F-fluoro-3, 4-dihydroxy-L-phenylalanine (18F-DOPA), involving the nucleophilic substitution of a diaryliodonium salt precursor with non-carrier-added 18F-fluoride, yielded a product with a specific activity that was 3 orders of magnitude higher than the product of the conventional synthesis method involving an electrophilic substitution of a trialkylstannane precursor with 18F2. We performed a direct comparison of high- and lowspecific- activity 18F-DOPA in a neuroendocrine tumor model to determine whether this difference in specific activity has implications for the biologic behavior and imaging properties of 18F-DOPA.Methods: 18F-DOPA was produced via the novel synthesis method, yielding 18F-DOPA-H with a high specific activity (35, 050 ± 4, 000 GBq/mmol). This product was compared in several experiments with conventional 18F-DOPA-L with a low specific activity (11 ± 2 GBq/mmol). In vitro accumulation experiments with the human pancreatic neuroendocrine tumor cell line BON-1 were performed at both 0°C and 37°C and at 37°C in the presence of pharmacologic inhibitors of proteins involved in the uptake mechanism of 18FDOPA. Small-animal PET experiments were performed in athymic nude mice bearing a BON-1 tumor xenograft.Results: At 37°C, the uptake of both 18F-DOPA-H and 18F-DOPA-L did not differ significantly during a 60-min accumulation experiment in BON-1 cells. At 0°C, the uptake of 18F-DOPA-L was significantly decreased, whereas the lower temperature did not alter the uptake of 18FDOPA- H. The pharmacologic inhibitors carbidopa and tetrabenazine also revealed differential effects between the 2 types of 18FDOPA in the 60-min accumulation experiment. The small-animal PET experiments did not show any significant differences in distribution and metabolism of 18F-DOPA-H and 18F-DOPA-L in carbidopapretreated mice.Conclusion: The advantages of the novel synthesis of 18F-DOPA, which relies on nucleophilic fluorination of a diaryliodonium salt precursor, lie in the simplicity of the synthesis method, compared with the conventional, electrophilic approach and in the reduced mass of administered, pharmacologically active 19F-DOPA. 18F-DOPA-H demonstrated comparable imaging properties in an in vivo model for neuroendocrine tumors, despite the fact that the injected mass of material was 3 orders of magnitude less than 18F-DOPA-L.

KW - Diaryliodonium salt

KW - F

KW - F-DOPA

KW - Neuroendocrine tumors

KW - PET

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