Cole, Graham B. Keum, Gyochang Liu, Jie Small, Gary W. Satyamurthy, Nagichettiar Kepe, Vladimir Barrio, Jorge R. 2024-01-20T19:32:16Z 2024-01-20T19:32:16Z 2021-09-01 2010-04-06 0027-8424 https://pubs.kist.re.kr/handle/201004/131548 This work focuses on the development of specific substrates for estrogen sulfotransferase (SULT1E1) to produce molecular imaging probes for this enzyme. SULT1E1 is a key enzyme in estrogen homeostasis, playing a central role in the prevention and development of human disease. In vitro sulfation assays showed alkyl and aryl substitutions to a fused heterocyclic system modeled after beta-naphthol (beta N), based on compounds that interact with the estrogen receptor, rendered several molecules with enhanced specificity for SULT1E1 over SULT1A1*1, SULT1A1*2, SULT1A3, and SULT2A1. Several 6-hydroxy-2-arylbenzothiazoles tested demonstrated excellent affinity-V-max/K-m ratios-and specificity for SULT1E1. Km values ranged from 0.12-2.36 mu M. A strong correlation was observed between polarity of the 4'-sustituent on the 2-aryl moiety (Hammett sigma(p)) and the log(V-max/K-m) (r = 0.964). Substrate sensitivity is influenced by the acidity of the 6-phenolic group demonstrated by correlating its H-1 NMR chemical shift (delta(OH)) with the log(V-max/K-m) (r = 0.963). Acidity is mediated by the electron withdrawing capacity of the 4'-substituent outlined by the correlation of the C-2 C-13 NMR chemical shift (delta(C2)) with the log(V-max/K-m) (r = 0.987). 2-[4-(Methylamino)phenyl]-6-hydroxybenzothiazole (2b) was radiolabeled with carbon-11 (C-11-(2b)) and used in vivo for microPET scanning and tissue metabolite identification. High PET signal was paralleled with the presence of radiolabeled C-11-(2b)-6-O-sulfate and the SULT1E1 protein detected by western blot. Because this and other members of this family presenting specificity for SULT1E1 can be labeled with carbon-11 or fluorine-18, in vivo assays of SULT1E1 functional activity are now feasible in humans. English NATL ACAD SCIENCES HUMAN CYTOSOLIC SULFOTRANSFERASES PITTSBURGH COMPOUND-B STEROID SULFATASE ALZHEIMERS-DISEASE ARYL SULFOTRANSFERASE CARCINOMA PET QUANTIFICATION INHIBITION MECHANISMS Specific estrogen sulfotransferase (SULT1E1) substrates and molecular imaging probe candidates Article 10.1073/pnas.0914904107 1 PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, v.107, no.14, pp.6222 - 6227 PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA 107 14 6222 6227 scie scopus 000276374400020 Multidisciplinary Sciences Science & Technology - Other Topics Article HUMAN CYTOSOLIC SULFOTRANSFERASES PITTSBURGH COMPOUND-B STEROID SULFATASE ALZHEIMERS-DISEASE ARYL SULFOTRANSFERASE CARCINOMA PET QUANTIFICATION INHIBITION MECHANISMS molecular imaging probes positron emission tomography Pittsburgh Compound B PIB F-18-Flutemetamol