Synthesis and basic evaluation of 7α-(3-[18F]fluoropropyl)-testosterone and 7α-(3-[18F]fluoropropyl)-dihydrotestosterone.
OBJECTIVE
7α-Substituted androgen derivatives may have the potential to visualize androgen receptors with positron emission tomography. In the present study, we synthesized fluoropropyl derivatives of 7α-(3-[18F]fluoropropyl)-testosterone ([18F]7) and 7α-(3-[18F]fluoropropyl)-dihydrotestosterone ([18F]15), and characterized their in vitro binding, in vivo biodistribution, and performed blocking studies in mature androgen deprived male rats.


METHODS
We synthesized [18F]7 and [18F]15. In vitro binding to recombinant rat AR ligand binding domain protein was determined using a competitive radiometric ligand-binding assay with the high-affinity synthetic androgen [17α-methyl-3H]-methyltrienolone ([3H]R1881). In vivo biodistribution was performed in mature male rats treated with diethylstilbestrol (chemical castration). A blocking study was performed by co-administration of dihydrotestosterone (36 µg/animal).


RESULTS
7α-(3-Fluoropropyl)-testosterone (7) and 7α-(3-fluoropropyl)-dihydrotestosterone (15) showed competitive binding to recombinant rat AR ligand binding domain protein. The IC50value of 15 (13.0 ± 3.3 nM) was higher than 7 (47.8 ± 10.0 nM). In contrast to the AR binding affinity, the ventral prostate uptake of [18F]7 and [18F]15 at 2 h post-injection was similar (0.07 % injected dose/g of tissue). A blocking study indicated that specific binding of [18F]15 is observed in the ventral prostate. [18F]7 and [18F]15 showed moderate levels of bone uptake, which indicates moderate metabolic de-fluorination in rodents.


CONCLUSIONS
[18F]15 is better than [18F]7 in terms of radiochemical yield, in vitro binding affinity, prostate specific binding and stability against in vivo metabolic de-fluorination. However, the net uptake level of [18F]15 in prostate might be insufficient for in vivo visualization. Although [18F]7 and [18F]15 improved in vivo stability against de-fluorination, other basic characterization data in rodents were not superior to the current standard tracer 16β-[18F]fluoro-5α-dihydrotestosterone. It is also revealed that the shorter side chain length of 7α-[18F]fluoromethyl-dihydrotestosterone is superior to the longer three carbon chain in [18F]15, in terms of net prostate uptake and in vivo metabolic stability.
Research Team for Neuroimaging, Tokyo Metropolitan Institute of Gerontology, 35-2 Sakae-cho, Itabashi-ku, Tokyo, 173-0015, Japan.|Research Institute for Science and Engineering, Waseda University, Tokyo, Japan.|Department of Immunology and Pathology, Research Institute of National Center for Global Health and Medicine, Ichikawa, Japan.
Mayumi
M
Okamoto
School of Advanced Science and Engineering, Waseda University, Tokyo, Japan.
Kyosuke
K
Naka
Research Team for Neuroimaging, Tokyo Metropolitan Institute of Gerontology, 35-2 Sakae-cho, Itabashi-ku, Tokyo, 173-0015, Japan.|Institute for Cyclotron and Drug Discovery Research, Southern Tohoku Research Institute of Neuroscience, Koriyama, Japan.|Department of Biofunctional Imaging, Fukushima Medical University, Fukushima, Japan.
Kiichi
K
Ishiwata
Research Institute for Science and Engineering, Waseda University, Tokyo, Japan.|School of Advanced Science and Engineering, Waseda University, Tokyo, Japan.
Isao
I
Shimizu
Research Team for Neuroimaging, Tokyo Metropolitan Institute of Gerontology, 35-2 Sakae-cho, Itabashi-ku, Tokyo, 173-0015, Japan. toyohara@pet.tmig.or.jp.
Jun
http://orcid.org/0000-0003-4721-405X
J
Toyohara
D000728:Androgens / Q000172:deficiency; D000818:Animals; D060326:Chemistry Techniques, Synthetic; D013196:Dihydrotestosterone / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism* / Q000493:pharmacokinetics; D008297:Male; D011854:Radiochemistry; D051381:Rats; D011944:Receptors, Androgen / Q000378:metabolism; D013739:Testosterone / Q000031:analogs & derivatives* / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism* / Q000493:pharmacokinetics; D014018:Tissue Distribution
C000613944:7-(3-fluoropropyl)dihydrotestosterone; C000613943:7-(3-fluoropropyl)testosterone; D000728:Androgens; D011944:Receptors, Androgen; D013196:Dihydrotestosterone; D013739:Testosterone
7α-(3-[18F]Fluoropropyl)-dihydrotestosterone; 7α-(3-[18F]Fluoropropyl)-testosterone; Androgen receptor; Positron emission tomography