Synthesis and biological evaluation of [18F]bicalutamide, 4-[76Br]bromobicalutamide, and 4-[76Br]bromo-thiobicalutamide as non-steroidal androgens for prostate cancer imaging.
Androgen receptors (AR) are overexpressed in most primary and metastatic prostate cancers. To develop a nonsteroidal AR-mediated imaging agent, we synthesized and radiolabeled several analogs of the potent antiandrogen bicalutamide: [18F]bicalutamide, 4-[76Br]bromobicalutamide, and [76Br]bromo-thiobicalutamide. Two of these analogs, 4-[76Br]bromobicalutamide and [76Br]bromo-thiobicalutamide, were found to have a substantially increased affinity for the androgen receptor (AR) compared to that of bicalutamide. The synthesis of [18F]bicalutamide utilized a pseudocarrier approach to effect addition of a carbanion generated from tracer-level amounts of a radiolabeled precursor to an unlabeled carbonyl precursor. 4-[76Br]Bromobicalutamide and [76Br]bromo-thiobicalutamide were labeled through electrophilic bromination of a tributylstannane precursor. The former could be prepared in high specific activity, and its tissue distribution was tested in vivo. Androgen target tissue uptake was evident in castrated adult male rats; however, in DES-treated, AR-positive, tumor-bearing male mice, tumor uptake was low.
Parent
Ephraim E
EE
Department of Chemistry, University of Illinois, 600 South Mathews Avenue, Urbana, Illinois 61801, USA.
Dence
Carmen S
CS
Jenks
Carl
C
Sharp
Terry L
TL
Welch
Michael J
MJ
Katzenellenbogen
John A
JA
D000726:Androgen Antagonists / Q000138:chemical synthesis* / Q000737:chemistry / Q000493:pharmacokinetics; D000813:Anilides / Q000138:chemical synthesis* / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology; D000818:Animals; D001967:Bromine Radioisotopes; D005462:Fluorine Radioisotopes; D007553:Isotope Labeling; D008024:Ligands; D008297:Male; D051379:Mice; D009368:Neoplasm Transplantation; D009570:Nitriles / Q000138:chemical synthesis* / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology; D011471:Prostatic Neoplasms / Q000000981:diagnostic imaging*; D011869:Radioligand Assay; D011877:Radionuclide Imaging; D019275:Radiopharmaceuticals / Q000138:chemical synthesis* / Q000737:chemistry / Q000493:pharmacokinetics; D051381:Rats; D017207:Rats, Sprague-Dawley; D011944:Receptors, Androgen / Q000378:metabolism; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D014018:Tissue Distribution; D014105:Tosyl Compounds / Q000138:chemical synthesis* / Q000737:chemistry / Q000493:pharmacokinetics
C518988:4-bromobicalutamide; C518989:4-bromothiobicalutamide; D000726:Androgen Antagonists; D000813:Anilides; D001967:Bromine Radioisotopes; D005462:Fluorine Radioisotopes; D008024:Ligands; D009570:Nitriles; D019275:Radiopharmaceuticals; D011944:Receptors, Androgen; D014105:Tosyl Compounds; C053541:bicalutamide