In vivo imaging of brain androgen receptors in rats: a [(18)F]FDHT PET study

M. A. Khayum; J. Doorduin; Ines Farinha Antunes; Chantal Kwizera; R. Zijlma; J. A. den Boer; R. A. J. O. Dierckx; E. F. J.  de Vries

doi:10.1016/j.nucmedbio.2015.02.003

In vivo imaging of brain androgen receptors in rats: a [(18)F]FDHT PET study

M. A. Khayum, J. Doorduin, Ines Farinha Antunes, Chantal Kwizera, R. Zijlma, J. A. den Boer, R. A. J. O. Dierckx, E. F. J. de Vries

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Abstract

INTRODUCTION: Steroid hormones like androgens play an important role in the development and maintenance of several brain functions. Androgens can act through androgen receptors (AR) in the brain. This study aims to demonstrate the feasibility of positron emission tomography (PET) with 16β-[(18)F]fluoro-5α-dihydrotestosterone ([(18)F]FDHT) to image AR expression in the brain.

METHODS: Male Wistar rats were either orchiectomized to inhibit endogenous androgen production or underwent sham-surgery. Fifteen days after surgery, rats were subjected to a 90-min dynamic [(18)F]FDHT PET scan with arterial blood sampling. In a subset of orchiectomized rats, 1mg/kg dihydrotestosterone was co-injected with the tracer in order to saturate the AR. Plasma samples were analyzed for the presence of radioactive metabolites by radio-TLC. Pharmacokinetic modeling was performed to quantify brain kinetics of the tracer. After the PET scan, the animals were terminated for ex-vivo biodistribution.

RESULTS: PET imaging and ex vivo biodistribution studies showed low [(18)F]FDHT uptake in all brain regions, except pituitary. [(18)F]FDHT uptake in the surrounding cranial bones was high and increased over time. [(18)F]FDHT was rapidly metabolized in rats. Metabolism was significantly faster in orchiectomized rats than in sham-orchiectomized rats. Quantitative analysis of PET data indicated substantial spill-over of activity from cranial bones into peripheral brain regions, which prevented further analysis of peripheral brain regions. Logan graphical analysis and kinetic modeling using 1- and 2-tissue compartment models showed reversible and homogenously distributed tracer uptake in central brain regions. [(18)F]FDHT uptake in the brain could not be blocked by endogenous androgens or administration of dihydrotestosterone.

CONCLUSION: The results of this study indicate that imaging of AR availability in rat brain with [(18)F]FDHT PET is not feasible. The low AR expression in the brain, the rapid metabolism of [(18)F]FDHT in rats and the poor brain penetration of the tracer likely contributed to the poor performance of [(18)F]FDHT PET in this study.

Original language	English
Pages (from-to)	561-569
Number of pages	9
Journal	Nuclear Medicine and Biology
Volume	42
Issue number	6
DOIs	https://doi.org/10.1016/j.nucmedbio.2015.02.003
Publication status	Published - Jun-2015

Keywords

16 beta-[(18) F]fluoro-5 alpha-dihydrotestosterone ([F-18]FDHT)
Androgen receptor
Small animal imaging
Neuroimaging
Positron emission tomography
3-BETA-HYDROXYSTEROID DEHYDROGENASE
ANTERIOR-PITUITARY
MESSENGER-RNA
TESTOSTERONE
MEN
CELLS
DIHYDROTESTOSTERONE
EXPRESSION
BINDING
CANCER

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In vivo imaging of brain androgen receptors in rats a [(18)F]FDHTFinal publisher's version, 653 KBLicence: Elsevier

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@article{c8c9d3746edd4bb79a84ff1b4d2bf7e2,

title = "In vivo imaging of brain androgen receptors in rats: a [(18)F]FDHT PET study",

abstract = "INTRODUCTION: Steroid hormones like androgens play an important role in the development and maintenance of several brain functions. Androgens can act through androgen receptors (AR) in the brain. This study aims to demonstrate the feasibility of positron emission tomography (PET) with 16β-[(18)F]fluoro-5α-dihydrotestosterone ([(18)F]FDHT) to image AR expression in the brain.METHODS: Male Wistar rats were either orchiectomized to inhibit endogenous androgen production or underwent sham-surgery. Fifteen days after surgery, rats were subjected to a 90-min dynamic [(18)F]FDHT PET scan with arterial blood sampling. In a subset of orchiectomized rats, 1mg/kg dihydrotestosterone was co-injected with the tracer in order to saturate the AR. Plasma samples were analyzed for the presence of radioactive metabolites by radio-TLC. Pharmacokinetic modeling was performed to quantify brain kinetics of the tracer. After the PET scan, the animals were terminated for ex-vivo biodistribution.RESULTS: PET imaging and ex vivo biodistribution studies showed low [(18)F]FDHT uptake in all brain regions, except pituitary. [(18)F]FDHT uptake in the surrounding cranial bones was high and increased over time. [(18)F]FDHT was rapidly metabolized in rats. Metabolism was significantly faster in orchiectomized rats than in sham-orchiectomized rats. Quantitative analysis of PET data indicated substantial spill-over of activity from cranial bones into peripheral brain regions, which prevented further analysis of peripheral brain regions. Logan graphical analysis and kinetic modeling using 1- and 2-tissue compartment models showed reversible and homogenously distributed tracer uptake in central brain regions. [(18)F]FDHT uptake in the brain could not be blocked by endogenous androgens or administration of dihydrotestosterone.CONCLUSION: The results of this study indicate that imaging of AR availability in rat brain with [(18)F]FDHT PET is not feasible. The low AR expression in the brain, the rapid metabolism of [(18)F]FDHT in rats and the poor brain penetration of the tracer likely contributed to the poor performance of [(18)F]FDHT PET in this study.",

keywords = "16 beta-[(18) F]fluoro-5 alpha-dihydrotestosterone ([F-18]FDHT), Androgen receptor, Small animal imaging, Neuroimaging, Positron emission tomography, 3-BETA-HYDROXYSTEROID DEHYDROGENASE, ANTERIOR-PITUITARY, MESSENGER-RNA, TESTOSTERONE, MEN, CELLS, DIHYDROTESTOSTERONE, EXPRESSION, BINDING, CANCER",

author = "Khayum, {M. A.} and J. Doorduin and {Farinha Antunes}, Ines and Chantal Kwizera and R. Zijlma and {den Boer}, {J. A.} and Dierckx, {R. A. J. O.} and {de Vries}, {E. F. J.}",

year = "2015",

month = jun,

doi = "10.1016/j.nucmedbio.2015.02.003",

language = "English",

volume = "42",

pages = "561--569",

journal = "Nuclear Medicine and Biology",

issn = "0969-8051",

publisher = "ELSEVIER SCIENCE INC",

number = "6",

}

TY - JOUR

T1 - In vivo imaging of brain androgen receptors in rats

T2 - a [(18)F]FDHT PET study

AU - Khayum, M. A.

AU - Doorduin, J.

AU - Farinha Antunes, Ines

AU - Kwizera, Chantal

AU - Zijlma, R.

AU - den Boer, J. A.

AU - Dierckx, R. A. J. O.

AU - de Vries, E. F. J.

PY - 2015/6

Y1 - 2015/6

N2 - INTRODUCTION: Steroid hormones like androgens play an important role in the development and maintenance of several brain functions. Androgens can act through androgen receptors (AR) in the brain. This study aims to demonstrate the feasibility of positron emission tomography (PET) with 16β-[(18)F]fluoro-5α-dihydrotestosterone ([(18)F]FDHT) to image AR expression in the brain.METHODS: Male Wistar rats were either orchiectomized to inhibit endogenous androgen production or underwent sham-surgery. Fifteen days after surgery, rats were subjected to a 90-min dynamic [(18)F]FDHT PET scan with arterial blood sampling. In a subset of orchiectomized rats, 1mg/kg dihydrotestosterone was co-injected with the tracer in order to saturate the AR. Plasma samples were analyzed for the presence of radioactive metabolites by radio-TLC. Pharmacokinetic modeling was performed to quantify brain kinetics of the tracer. After the PET scan, the animals were terminated for ex-vivo biodistribution.RESULTS: PET imaging and ex vivo biodistribution studies showed low [(18)F]FDHT uptake in all brain regions, except pituitary. [(18)F]FDHT uptake in the surrounding cranial bones was high and increased over time. [(18)F]FDHT was rapidly metabolized in rats. Metabolism was significantly faster in orchiectomized rats than in sham-orchiectomized rats. Quantitative analysis of PET data indicated substantial spill-over of activity from cranial bones into peripheral brain regions, which prevented further analysis of peripheral brain regions. Logan graphical analysis and kinetic modeling using 1- and 2-tissue compartment models showed reversible and homogenously distributed tracer uptake in central brain regions. [(18)F]FDHT uptake in the brain could not be blocked by endogenous androgens or administration of dihydrotestosterone.CONCLUSION: The results of this study indicate that imaging of AR availability in rat brain with [(18)F]FDHT PET is not feasible. The low AR expression in the brain, the rapid metabolism of [(18)F]FDHT in rats and the poor brain penetration of the tracer likely contributed to the poor performance of [(18)F]FDHT PET in this study.

AB - INTRODUCTION: Steroid hormones like androgens play an important role in the development and maintenance of several brain functions. Androgens can act through androgen receptors (AR) in the brain. This study aims to demonstrate the feasibility of positron emission tomography (PET) with 16β-[(18)F]fluoro-5α-dihydrotestosterone ([(18)F]FDHT) to image AR expression in the brain.METHODS: Male Wistar rats were either orchiectomized to inhibit endogenous androgen production or underwent sham-surgery. Fifteen days after surgery, rats were subjected to a 90-min dynamic [(18)F]FDHT PET scan with arterial blood sampling. In a subset of orchiectomized rats, 1mg/kg dihydrotestosterone was co-injected with the tracer in order to saturate the AR. Plasma samples were analyzed for the presence of radioactive metabolites by radio-TLC. Pharmacokinetic modeling was performed to quantify brain kinetics of the tracer. After the PET scan, the animals were terminated for ex-vivo biodistribution.RESULTS: PET imaging and ex vivo biodistribution studies showed low [(18)F]FDHT uptake in all brain regions, except pituitary. [(18)F]FDHT uptake in the surrounding cranial bones was high and increased over time. [(18)F]FDHT was rapidly metabolized in rats. Metabolism was significantly faster in orchiectomized rats than in sham-orchiectomized rats. Quantitative analysis of PET data indicated substantial spill-over of activity from cranial bones into peripheral brain regions, which prevented further analysis of peripheral brain regions. Logan graphical analysis and kinetic modeling using 1- and 2-tissue compartment models showed reversible and homogenously distributed tracer uptake in central brain regions. [(18)F]FDHT uptake in the brain could not be blocked by endogenous androgens or administration of dihydrotestosterone.CONCLUSION: The results of this study indicate that imaging of AR availability in rat brain with [(18)F]FDHT PET is not feasible. The low AR expression in the brain, the rapid metabolism of [(18)F]FDHT in rats and the poor brain penetration of the tracer likely contributed to the poor performance of [(18)F]FDHT PET in this study.

KW - 16 beta-[(18) F]fluoro-5 alpha-dihydrotestosterone ([F-18]FDHT)

KW - Androgen receptor

KW - Small animal imaging

KW - Neuroimaging

KW - Positron emission tomography

KW - 3-BETA-HYDROXYSTEROID DEHYDROGENASE

KW - ANTERIOR-PITUITARY

KW - MESSENGER-RNA

KW - TESTOSTERONE

KW - MEN

KW - CELLS

KW - DIHYDROTESTOSTERONE

KW - EXPRESSION

KW - BINDING

KW - CANCER

U2 - 10.1016/j.nucmedbio.2015.02.003

DO - 10.1016/j.nucmedbio.2015.02.003

M3 - Article

C2 - 25735222

SN - 0969-8051

VL - 42

SP - 561

EP - 569

JO - Nuclear Medicine and Biology

JF - Nuclear Medicine and Biology

IS - 6

ER -

In vivo imaging of brain androgen receptors in rats: a [(18)F]FDHT PET study

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