Synthesis, Radiosynthesis and in vitro Studies on Novel Hypoxia PET Tracers Incorporating [18F]FDR

Manuele Musolino; Ian N Fleming; Lutz F.  Schweiger; David O'hagan; Sergio Dall'Angelo; University Aberdeen

doi:10.1002/ejoc.202001670

Synthesis, Radiosynthesis and in vitro Studies on Novel Hypoxia PET Tracers Incorporating [18F]FDR

Manuele Musolino, Ian N Fleming, Lutz F. Schweiger, David O'hagan, Sergio Dall'Angelo^* (Corresponding Author), University Aberdeen^* (Corresponding Author)

^*Corresponding author for this work

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Abstract

We report the synthesis of five radiotracers incorporating different oxyamine spacers between the hypoxia-reactive 2-nitroimidazole moiety and the 5-[18F]-fluorodeoxyribose ([18F]FDR, 12) prosthetic group: three linear alkyl chains with 3, 5, 7 carbon atoms (15a-c), a cyclopropyl ring (15d) and a 1,4-disubstituted-1,2,3-triazole (15e). Experiments in hypoxic cells showed that 15d displays superior uptake kinetics – and similar selectivity for hypoxic cells – relative to the gold standard hypoxia tracers[18F]fluoroazomycin arabinoside ([18F]FAZA) and [18F]fluoromisonidazole ([18F]FMISO). Lipophilicity and structural rigidity have strong influence on the selectivity of tracers 15 towards hypoxic cells: the lead tracer 15d displays a logP = 0.38 and the most rigid spacer. A sixth radiotracer (15f), with a 2-H-imidazole replacing the 2-nitroimidazole moiety of 15d, was used to demonstrate that the cyclopropyl group does not play a meaningful role in the sensitivity towards hypoxia.

Original language	English
Pages (from-to)	1429-1439
Number of pages	11
Journal	European Journal of Organic Chemistry
Volume	2021
Issue number	9
Early online date	22 Feb 2021
DOIs	https://doi.org/10.1002/ejoc.202001670
Publication status	Published - 5 Mar 2021

Keywords

FDR
Hypoxia
Positron emission
Radiochemistry
Tomography

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title = "Synthesis, Radiosynthesis and in vitro Studies on Novel Hypoxia PET Tracers Incorporating [18F]FDR",

abstract = "We report the synthesis of five radiotracers incorporating different oxyamine spacers between the hypoxia-reactive 2-nitroimidazole moiety and the 5-[18F]-fluorodeoxyribose ([18F]FDR, 12) prosthetic group: three linear alkyl chains with 3, 5, 7 carbon atoms (15a-c), a cyclopropyl ring (15d) and a 1,4-disubstituted-1,2,3-triazole (15e). Experiments in hypoxic cells showed that 15d displays superior uptake kinetics – and similar selectivity for hypoxic cells – relative to the gold standard hypoxia tracers[18F]fluoroazomycin arabinoside ([18F]FAZA) and [18F]fluoromisonidazole ([18F]FMISO). Lipophilicity and structural rigidity have strong influence on the selectivity of tracers 15 towards hypoxic cells: the lead tracer 15d displays a logP = 0.38 and the most rigid spacer. A sixth radiotracer (15f), with a 2-H-imidazole replacing the 2-nitroimidazole moiety of 15d, was used to demonstrate that the cyclopropyl group does not play a meaningful role in the sensitivity towards hypoxia.",

keywords = "FDR, Hypoxia, Positron emission, Radiochemistry, Tomography",

author = "Manuele Musolino and Fleming, {Ian N} and Schweiger, {Lutz F.} and David O'hagan and Sergio Dall'Angelo and University Aberdeen",

note = "Funding Information: M.M. thanks SULSA for a PhD studentship. We gratefully acknowledge financial support from the EPSRC (grant EP/I034793/1). ",

year = "2021",

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doi = "10.1002/ejoc.202001670",

language = "English",

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TY - JOUR

T1 - Synthesis, Radiosynthesis and in vitro Studies on Novel Hypoxia PET Tracers Incorporating [18F]FDR

AU - Musolino, Manuele

AU - Fleming, Ian N

AU - Schweiger, Lutz F.

AU - O'hagan, David

AU - Dall'Angelo, Sergio

AU - Aberdeen, University

N1 - Funding Information: M.M. thanks SULSA for a PhD studentship. We gratefully acknowledge financial support from the EPSRC (grant EP/I034793/1).

PY - 2021/3/5

Y1 - 2021/3/5

N2 - We report the synthesis of five radiotracers incorporating different oxyamine spacers between the hypoxia-reactive 2-nitroimidazole moiety and the 5-[18F]-fluorodeoxyribose ([18F]FDR, 12) prosthetic group: three linear alkyl chains with 3, 5, 7 carbon atoms (15a-c), a cyclopropyl ring (15d) and a 1,4-disubstituted-1,2,3-triazole (15e). Experiments in hypoxic cells showed that 15d displays superior uptake kinetics – and similar selectivity for hypoxic cells – relative to the gold standard hypoxia tracers[18F]fluoroazomycin arabinoside ([18F]FAZA) and [18F]fluoromisonidazole ([18F]FMISO). Lipophilicity and structural rigidity have strong influence on the selectivity of tracers 15 towards hypoxic cells: the lead tracer 15d displays a logP = 0.38 and the most rigid spacer. A sixth radiotracer (15f), with a 2-H-imidazole replacing the 2-nitroimidazole moiety of 15d, was used to demonstrate that the cyclopropyl group does not play a meaningful role in the sensitivity towards hypoxia.

AB - We report the synthesis of five radiotracers incorporating different oxyamine spacers between the hypoxia-reactive 2-nitroimidazole moiety and the 5-[18F]-fluorodeoxyribose ([18F]FDR, 12) prosthetic group: three linear alkyl chains with 3, 5, 7 carbon atoms (15a-c), a cyclopropyl ring (15d) and a 1,4-disubstituted-1,2,3-triazole (15e). Experiments in hypoxic cells showed that 15d displays superior uptake kinetics – and similar selectivity for hypoxic cells – relative to the gold standard hypoxia tracers[18F]fluoroazomycin arabinoside ([18F]FAZA) and [18F]fluoromisonidazole ([18F]FMISO). Lipophilicity and structural rigidity have strong influence on the selectivity of tracers 15 towards hypoxic cells: the lead tracer 15d displays a logP = 0.38 and the most rigid spacer. A sixth radiotracer (15f), with a 2-H-imidazole replacing the 2-nitroimidazole moiety of 15d, was used to demonstrate that the cyclopropyl group does not play a meaningful role in the sensitivity towards hypoxia.

KW - FDR

KW - Hypoxia

KW - Positron emission

KW - Radiochemistry

KW - Tomography

U2 - 10.1002/ejoc.202001670

DO - 10.1002/ejoc.202001670

M3 - Article

VL - 2021

SP - 1429

EP - 1439

JO - European Journal of Organic Chemistry

JF - European Journal of Organic Chemistry

SN - 1434-193X

IS - 9

ER -

Synthesis, Radiosynthesis and in vitro Studies on Novel Hypoxia PET Tracers Incorporating [18F]FDR

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