Amino and iodotamoxifens: synthesis, estrogen receptor affinity and biodistribution.
Both geometrical isomers (E and Z) of an aminotamoxifen (2) have been prepared as precursors of the corresponding E and Z iodotamoxifens (1). The ability of E and Z-1 and 2 to compete with [3H]estradiol for estrogen receptors in rat uterine cytosol was measured relative to Z-tamoxifen and estradiol. The four tamoxifen derivatives showed affinities ranging from 50% to 1600% of that of tamoxifen. Under the same conditions, tamoxifen's relative binding affinity was 0.2% of that of estradiol. Preparative routes to the radioiodo-tamoxifens, [131I]-E and Z-1, were also developed and provided approximately 100 MBq of 'no carrier added' material in 40-60% radiochemical yield. Study of the biodistribution of these radioligands in tumor-bearing mice demonstrated significant radioactivity in the tumors and in the uterus. For [131I]-E-1, target to background ratios reached 28 for uterus/blood and 10 for tumor/blood; corresponding optimum ratios for [131I]-Z-1 were 10 and 5. A washout study using estradiol indicated selective uptake in the uterus of Swiss white mice. However, tumor uptake and image contrast in humans following intravenous administration of either [131I]-E or Z-1 were insufficient to allow diagnostic use of the radioiodotamoxifens.
Strickland
L A
LA
Department of Chemistry, University of Western Ontario, London, Canada.
Ponce
Y Z
YZ
Hunter
D H
DH
Zabel
P L
PL
Powe
J E
JE
Morrissey
G
G
Driedger
A A
AA
Chamberlain
M J
MJ
Tustanoff
E R
ER
D000368:Aged; D000818:Animals; D001943:Breast Neoplasms / Q000378:metabolism; D005260:Female; D006801:Humans; D066298:In Vitro Techniques; D007457:Iodine Radioisotopes; D007536:Isomerism; D008168:Lung / Q000378:metabolism; D051379:Mice; D008809:Mice, Inbred C3H; D008875:Middle Aged; D009374:Neoplasms, Experimental / Q000378:metabolism; D051381:Rats; D011919:Rats, Inbred Strains; D011960:Receptors, Estrogen / Q000378:metabolism*; D013670:Sodium Pertechnetate Tc 99m; D013629:Tamoxifen / Q000031:analogs & derivatives* / Q000378:metabolism* / Q000493:pharmacokinetics; D014018:Tissue Distribution; D014599:Uterus / Q000187:drug effects / Q000378:metabolism
D007457:Iodine Radioisotopes; D011960:Receptors, Estrogen; D013629:Tamoxifen; D013670:Sodium Pertechnetate Tc 99m