Improving metabolic stability of fluorine-18 labeled verapamil analogs

Renske M Raaphorst; Gert Luurtsema; Cindy J Schokker; Khaled A Attia; Robert C Schuit; Philip H Elsinga; Adriaan A Lammertsma; Albert D Windhorst

doi:https://doi.org/10.1016/j.nucmedbio.2018.06.009

Improving metabolic stability of fluorine-18 labeled verapamil analogs

Renske M Raaphorst, Gert Luurtsema, Cindy J Schokker, Khaled A Attia, Robert C Schuit, Philip H Elsinga, Adriaan A Lammertsma, Albert D Windhorst

Research output: Contribution to journal › Article › Academic › peer-review

6 Citations (Scopus)

Abstract

INTRODUCTION: Fluorine-18 labeled positron emission tomography (PET) tracers were developed to obtain more insight into the function of P-glycoprotein (P-gp) in relation to various conditions. They allow research in facilities without a cyclotron as they can be transported with a half-life of 110 min. As the metabolic stability of previously reported tracers [18F]1 and [18F]2 was poor, the purpose of this study was to improve this stability using deuterium substitution, creating verapamil analogs [18F]1-d4, [18F]2-d4, [18F]3-d3 and [18F]3-d7.

METHODS: The following deuterium containing tracers were synthesized and evaluated in mice and rats: [18F]1-d4, [18F]2-d4, [18F]3-d3 and [18F]3-d7.

RESULTS: The deuterated analogs [18F]2-d4, [18F]3-d3 and [18F]3-d7 showed increased metabolic stability compared with their non-deuterated counterparts. The increased metabolic stability of the methyl containing analogs [18F]3-d3 and [18F]3-d7 might be caused by steric hindrance for enzymes.

CONCLUSION: The striking similar in vivo behavior of [18F]3-d7 to that of (R)-[11C]verapamil, and its improved metabolic stability compared with the other fluorine-18 labeled tracers synthesized, supports the potential clinical translation of [18F]3-d7 as a PET radiopharmaceutical for P-gp evaluation.

Original language	English
Pages (from-to)	47-56
Number of pages	10
Journal	Nuclear medicine and biology
Volume	64-65
DOIs	https://doi.org/10.1016/j.nucmedbio.2018.06.009
Publication status	Published - 30 Jul 2018

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https://doi.org/10.1016/j.nucmedbio.2018.06.009

Cite this

@article{9c4eb5b446d8490b97a18f511501d2c0,

title = "Improving metabolic stability of fluorine-18 labeled verapamil analogs",

abstract = "INTRODUCTION: Fluorine-18 labeled positron emission tomography (PET) tracers were developed to obtain more insight into the function of P-glycoprotein (P-gp) in relation to various conditions. They allow research in facilities without a cyclotron as they can be transported with a half-life of 110 min. As the metabolic stability of previously reported tracers [18F]1 and [18F]2 was poor, the purpose of this study was to improve this stability using deuterium substitution, creating verapamil analogs [18F]1-d4, [18F]2-d4, [18F]3-d3 and [18F]3-d7.METHODS: The following deuterium containing tracers were synthesized and evaluated in mice and rats: [18F]1-d4, [18F]2-d4, [18F]3-d3 and [18F]3-d7.RESULTS: The deuterated analogs [18F]2-d4, [18F]3-d3 and [18F]3-d7 showed increased metabolic stability compared with their non-deuterated counterparts. The increased metabolic stability of the methyl containing analogs [18F]3-d3 and [18F]3-d7 might be caused by steric hindrance for enzymes.CONCLUSION: The striking similar in vivo behavior of [18F]3-d7 to that of (R)-[11C]verapamil, and its improved metabolic stability compared with the other fluorine-18 labeled tracers synthesized, supports the potential clinical translation of [18F]3-d7 as a PET radiopharmaceutical for P-gp evaluation.",

author = "Raaphorst, {Renske M} and Gert Luurtsema and Schokker, {Cindy J} and Attia, {Khaled A} and Schuit, {Robert C} and Elsinga, {Philip H} and Lammertsma, {Adriaan A} and Windhorst, {Albert D}",

year = "2018",

month = jul,

day = "30",

doi = "https://doi.org/10.1016/j.nucmedbio.2018.06.009",

language = "English",

volume = "64-65",

pages = "47--56",

journal = "Nuclear medicine and biology",

issn = "0969-8051",

publisher = "Elsevier Inc.",

}

TY - JOUR

T1 - Improving metabolic stability of fluorine-18 labeled verapamil analogs

AU - Raaphorst, Renske M

AU - Luurtsema, Gert

AU - Schokker, Cindy J

AU - Attia, Khaled A

AU - Schuit, Robert C

AU - Elsinga, Philip H

AU - Lammertsma, Adriaan A

AU - Windhorst, Albert D

PY - 2018/7/30

Y1 - 2018/7/30

N2 - INTRODUCTION: Fluorine-18 labeled positron emission tomography (PET) tracers were developed to obtain more insight into the function of P-glycoprotein (P-gp) in relation to various conditions. They allow research in facilities without a cyclotron as they can be transported with a half-life of 110 min. As the metabolic stability of previously reported tracers [18F]1 and [18F]2 was poor, the purpose of this study was to improve this stability using deuterium substitution, creating verapamil analogs [18F]1-d4, [18F]2-d4, [18F]3-d3 and [18F]3-d7.METHODS: The following deuterium containing tracers were synthesized and evaluated in mice and rats: [18F]1-d4, [18F]2-d4, [18F]3-d3 and [18F]3-d7.RESULTS: The deuterated analogs [18F]2-d4, [18F]3-d3 and [18F]3-d7 showed increased metabolic stability compared with their non-deuterated counterparts. The increased metabolic stability of the methyl containing analogs [18F]3-d3 and [18F]3-d7 might be caused by steric hindrance for enzymes.CONCLUSION: The striking similar in vivo behavior of [18F]3-d7 to that of (R)-[11C]verapamil, and its improved metabolic stability compared with the other fluorine-18 labeled tracers synthesized, supports the potential clinical translation of [18F]3-d7 as a PET radiopharmaceutical for P-gp evaluation.

AB - INTRODUCTION: Fluorine-18 labeled positron emission tomography (PET) tracers were developed to obtain more insight into the function of P-glycoprotein (P-gp) in relation to various conditions. They allow research in facilities without a cyclotron as they can be transported with a half-life of 110 min. As the metabolic stability of previously reported tracers [18F]1 and [18F]2 was poor, the purpose of this study was to improve this stability using deuterium substitution, creating verapamil analogs [18F]1-d4, [18F]2-d4, [18F]3-d3 and [18F]3-d7.METHODS: The following deuterium containing tracers were synthesized and evaluated in mice and rats: [18F]1-d4, [18F]2-d4, [18F]3-d3 and [18F]3-d7.RESULTS: The deuterated analogs [18F]2-d4, [18F]3-d3 and [18F]3-d7 showed increased metabolic stability compared with their non-deuterated counterparts. The increased metabolic stability of the methyl containing analogs [18F]3-d3 and [18F]3-d7 might be caused by steric hindrance for enzymes.CONCLUSION: The striking similar in vivo behavior of [18F]3-d7 to that of (R)-[11C]verapamil, and its improved metabolic stability compared with the other fluorine-18 labeled tracers synthesized, supports the potential clinical translation of [18F]3-d7 as a PET radiopharmaceutical for P-gp evaluation.

U2 - https://doi.org/10.1016/j.nucmedbio.2018.06.009

DO - https://doi.org/10.1016/j.nucmedbio.2018.06.009

M3 - Article

C2 - 30056279

SN - 0969-8051

VL - 64-65

SP - 47

EP - 56

JO - Nuclear medicine and biology

JF - Nuclear medicine and biology

ER -