Direct One-Step18F-Labeling of Peptides via Nucleophilic

Aromatic Substitution
Jessica Becaud, Linjing Mu, Mylne Karramkam, Pius A. Schubiger, Simon M.
Ametamey*, Keith Graham,Timo Stellfeld, Lutz Lehmann, Sandra Borkowski, Dietmar
Berndorf, Ludger Dinkelborg, Ananth Srinivasan*, Ren Smits and Beate Koksch
Center for Radiopharmaceutical Science of ETH, PSI and USZ, Department of Chemistry and Applied
Biosciences, ETH Zurich, CH-8093 Zurich, Switzerland, Bayer Schering Pharma AG, Global Drug
Discovery, D-13342 Berlin, Germany, Department of Chemistry and Biochemistry - Organic Chemistry, FU
Berlin, Takustrae 3, D-14195 Berlin, Germany
Bioconjugate Chem., 2009, 20 (12), pp 22542261
DOI: 10.1021/bc900240z
Publication Date (Web): November 18, 2009
Copyright 2009 American Chemical Society
* Corresponding author. Center for Radiopharmaceutical Science of ETH, PSI and USZ, ETH Hnggerberg D-CHAB
IPW HCI H427, Wolfgang-Pauli-Strasse 10, CH-8093 Zurich, Switzerland. Tel.: +41 44 633 74 63; fax: +41 44 633 13
67. E-mail address:simon.ametamey@pharma.ethz.ch (S. Ametamey).,
ETH Zurich.
,
Bayer Schering Pharma AG.
,
FU Berlin.

Abstract
Methods for the radiolabeling molecules of interest with [18F]-fluoride need to be rapid, convenient,
and efficient. Numerous [18F]-labeled prosthetic groups, e.g., N-succinimidyl 4 [18F]-fluorobenzoate
([18F]-SFB), 4-azidophenacyl-[18F]-fluoride ([18F]-APF), and 1-(3-(2-[18F]fluoropyridin-3yloxy)propyl)pyrrole-2,5-dione ([18F]-FpyMe), for conjugating to biomolecules have been developed.
As the synthesis of these prosthetic groups usually requires multistep procedures, there is still a
need for direct methods for the nucleophilic [18F]-fluorination of biomolecules. We report here on the
development of a procedure based on the trimethylammonium (TMA) leaving group attached to an
aromatic ring and activated with different electron-withdrawing groups (EWGs). A series of model
compounds containing different electron-withdrawing substituents, a trimethylammonium leaving
group, and carboxylic functionality for subsequent coupling to peptides were designed and
synthesized. The optimal model compound, 2-cyano-4-(methoxycarbonyl)-N,N,Ntrimethylbenzenaminium trifluoromethanesulfonate, was converted to carboxylic acid and coupled to
peptides. The results of the one-step [18F]-fluorination of tetrapeptides and bombesin peptides show

that the direct18F-labeling of peptides is feasible under mild conditions and in good radiochemical
yields.

Hyperbranched Poly(arylene ether amide) via Nucleophilic Aromatic Substitution Reaction

1.

Insik In and

2.

Sang Youl Kim*

Article first published online: 12 SEP 2005

DOI: 10.1002/macp.200500167
Copyright 2005 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim

Issue

Macromolecular Chemistry and Physics

Volume 206, Issue 18, pages 18621869, September 23, 2005

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Keywords:

hyperbranched polymers;

polyamides;

step-growth polymerization

Abstract

Polymerization of AB2 and A2B-type monomers.

Summary: New hyperbranched poly(arylene ether amides) with fluorine or hydroxy end groups were synthesized
from AB2 or A2B type monomers via a nucleophilic aromatic substitution (SNAr) reaction. Monomer syntheses were
facilitated by chemo-selective amidation reactions, and even a direct synthesis of hyperbranched polymer was
possible without isolation of the monomer. The resulting hyperbranched poly(arylene ether amides) showed highly
branched characteristics (DB=0.430.53), high glass transition temperatures (Tg>220C), and high thermal stability
(Td10>420C). All hyperbranched polymers were readily soluble in aprotic polar solvents such as DMF, DMSO, and
NMP regardless of the end groups. Such a similar solubility pattern may result from the high amide contents and
longer branching distances between adjacent branching points in these hyperbranched polymer backbones.

Ionic Liquids as Designer Solvents for Nucleophilic Aromatic

Substitutions
Ian Newington , Juan M. Perez-Arlandis , and Tom Welton *
GE Healthcare Bio-Sciences, The Grove Centre, White Lion Road Amersham, HP7 9LL, and Imperial
College of Science Technology and Medicine, South Kensington, London SW7 2AZ, UK
Org. Lett., 2007, 9 (25), pp 52475250
DOI: 10.1021/ol702435f
Publication Date (Web): November 15, 2007
Copyright 2007 American Chemical Society

Abstract

Ionic liquids were designed to optimize the nucleophilic aromatic substitution reaction of an activated
aniline with an activated arylhalide. The design was achieved by selecting the anions on the basis of
calculations of the gas-phase basicity of their conjugate acids.

Study of Aromatic Nucleophilic Substitution with Amines on

Nitrothiophenes in Room-Temperature Ionic Liquids: Are the Different
Effects on the Behavior of para-Like and ortho-Like Isomers on Going
from Conventional Solvents to Room-Temperature Ionic Liquids
Related to Solvation Effects?
Francesca D'Anna ,* Vincenzo Frenna , Renato Noto ,* Vitalba Pace , and Domenico Spinelli *; ;
Dipartimento di Chimica Organica E. Patern, Universit degli Studi di Palermo, Viale delle ScienzeParco d'Orleans II, 90128 Palermo, Italy, and Dipartimento di Chimica Organica A. Mangini, Universit
degli Studi di Bologna, Via S. Giacomo 11, 40126 Bologna, Italy
J. Org. Chem., 2006, 71 (14), pp 51445150
DOI: 10.1021/jo060435q
Publication Date (Web): June 10, 2006
Copyright 2006 American Chemical Society

Abstract

The kinetics of the nucleophilic aromatic substitution of some 2-L-5-nitrothiophenes (para-like

isomers) with three different amines (pyrrolidine, piperidine, and morpholine) were studied in three
room-temperature ionic liquids ([bmim][BF4], [bmim][PF6], and [bm2im][BF4], where bmim = 1-butyl-3methylimidazolium and bm2im = 1-butyl-2,3-dimethylimidazolium). To calculate thermodynamic
parameters, a useful instrument to gain information concerning reagentsolvent interactions, the
reaction was carried out over the temperature range 293313 K. The reaction occurs faster in ionic
liquids than in conventional solvents (methanol, benzene), a dependence of rate constants on amine
concentration similar to that observed in methanol, suggesting a parallel behavior. The above
reaction also was studied with 2-bromo-3-nitrothiophene, an ortho-like derivative able to give peculiar
intramolecular interactions in the transition state, which are strongly affected by the reaction medium.

Nucleophilic Substitution Reactions of Alcohols with Use of

Montmorillonite Catalysts as Solid Brnsted Acids
Ken Motokura , Nobuaki Nakagiri , Tomoo Mizugaki , Kohki Ebitani , and Kiyotomi Kaneda *
Department of Materials Engineering Science, Graduate School of Engineering Science and Research
Center for Solar Energy Chemistry, Osaka University, 1-3 Machikaneyana, Toyonaka, Osaka 560-8531,
Japan
J. Org. Chem., 2007, 72 (16), pp 60066015
DOI: 10.1021/jo070416w
Publication Date (Web): July 13, 2007
Copyright 2007 American Chemical Society

Abstract

We have developed an environmentally benign synthetic approach to nucleophilic substitution

reactions of alcohols that minimizes or eliminates the formation of byproducts, resulting in a highly
atom-efficient chemical process. Proton- and metal-exchanged montmorillonites (H- and M n+-mont)
were prepared easily by treating Na+-mont with an aqueous solution of hydrogen chloride or metal
salt, respectively. The H-mont possessed outstanding catalytic activity for nucleophilic substitution
reactions of a variety of alcohols with anilines, because the unique acidity of the H-mont catalyst
effectively prevents the neutralization by the basic anilines. In addition, amides, indoles, 1,3dicarbonyl compounds, and allylsilane act as nucleophiles for the H-mont-catalyzed substitutions of
alcohols, which allowed efficient formation of various CN and CC bonds. The solid H-mont was
reusable without any appreciable loss in its catalytic activity and selectivity. Especially, an Al 3+-mont
showed high catalytic activity for the -benzylation of 1,3-dicarbonyl compounds with primary
alcohols due to cooperative catalysis between a protonic acid site and a Lewis acidic Al 3+ species in
its interlayer spaces.