title: An efficient and practical synthesis of [2-(11)C]indole via superfast nucleophilic [(11)C]cyanation and RANEY® Nickel catalyzed reductive cyclization.
abstract: A rapid method for the synthesis of carbon-11 radiolabeled indole was developed using a sub-nanomolar quantity of no-carrier-added [(11)C]cyanide as radio-precursor. Based upon a reported synthesis of 2-(2-nitrophenyl)acetonitrile (), a highly reactive substrate 2-nitrobenzyl bromide () was evaluated for nucleophilic [(11)C]cyanation. Additionally, related reaction conditions were explored with the goal of obtaining of highly reactive 2-(2-nitrophenyl)-[1-(11)C]acetonitrile () while inhibiting its rapid conversion to 2,3-bis(2-nitrophenyl)-[1-(11)C]propanenitrile (). Next, a RANEY® Nickel catalyzed reductive cyclization method was utilized for synthesizing the desired [2-(11)C]indole with hydrazinium monoformate as the active reducing agent. Extensive and iterative screening of basicity, temperature and stoichiometry was required to overcome the large stoichiometry bias that favored 2-nitrobenzylbromide () over [(11)C]cyanide, which both caused further alkylation of the desired nitrile and poisoned the RANEY® Nickel catalyst. The result is an efficient two-step, streamlined method to reliably synthesize [2-(11)C]indole with an entire radiochemical yield of 21 ± 2.2% (n = 5, ranging from 18-24%). The radiochemical purity of the final product was >98% and specific activity was 176 ± 24.8 GBq μmol(-1) (n = 5, ranging from 141-204 GBq μmol(-1)). The total radiosynthesis time including product purification by semi-preparative HPLC was 50-55 min from end of cyclotron bombardment.
authors.affiliation: Biological, Environmental & Climate Sciences Department, Brookhaven National Laboratory, Upton, NY 11973, USA. wqu@bnl.gov and Department of Chemistry, Stony Brook University, Stony Brook, NY 11794, USA.
authors.forename: So Jeong
authors.initials: SJ
authors.lastname: Lee
authors.affiliation: Biological, Environmental & Climate Sciences Department, Brookhaven National Laboratory, Upton, NY 11973, USA. wqu@bnl.gov.
authors.forename: Joanna S
authors.initials: JS
authors.lastname: Fowler
authors.affiliation: Biological, Environmental & Climate Sciences Department, Brookhaven National Laboratory, Upton, NY 11973, USA. wqu@bnl.gov.
authors.forename: David
authors.initials: D
authors.lastname: Alexoff
authors.affiliation: Biological, Environmental & Climate Sciences Department, Brookhaven National Laboratory, Upton, NY 11973, USA. wqu@bnl.gov.
authors.forename: Michael
authors.initials: M
authors.lastname: Schueller
authors.affiliation: Biological, Environmental & Climate Sciences Department, Brookhaven National Laboratory, Upton, NY 11973, USA. wqu@bnl.gov.
authors.forename: Dohyun
authors.initials: D
authors.lastname: Kim
authors.affiliation: Biological, Environmental & Climate Sciences Department, Brookhaven National Laboratory, Upton, NY 11973, USA. wqu@bnl.gov and Institut für Kernchemie, Johannes Gutenberg-Universität, D-55128, Mainz, Germany.
authors.forename: Alexander
authors.initials: A
authors.lastname: Nauth
authors.affiliation: Biological, Environmental & Climate Sciences Department, Brookhaven National Laboratory, Upton, NY 11973, USA. wqu@bnl.gov and Institut für Kernchemie, Johannes Gutenberg-Universität, D-55128, Mainz, Germany.
authors.forename: Carina
authors.initials: C
authors.lastname: Weber
authors.affiliation: Biological, Environmental & Climate Sciences Department, Brookhaven National Laboratory, Upton, NY 11973, USA. wqu@bnl.gov.
authors.forename: Sung Won
authors.initials: SW
authors.lastname: Kim
authors.affiliation: Biological, Environmental & Climate Sciences Department, Brookhaven National Laboratory, Upton, NY 11973, USA. wqu@bnl.gov and Athinoula A. Martinos Center for Biomedical Imaging, Department of Radiology, Massachusetts General Hospital, Harvard Medical School, Charlestown, Massachusetts 02129, USA.
authors.forename: Jacob M
authors.initials: JM
authors.lastname: Hooker
authors.affiliation: Athinoula A. Martinos Center for Biomedical Imaging, Department of Radiology, Massachusetts General Hospital, Harvard Medical School, Charlestown, Massachusetts 02129, USA.
authors.forename: Ling
authors.initials: L
authors.lastname: Ma
authors.affiliation: Biological, Environmental & Climate Sciences Department, Brookhaven National Laboratory, Upton, NY 11973, USA. wqu@bnl.gov.
authors.forename: Wenchao
authors.initials: W
authors.lastname: Qu