Communication
Abstract: A simple Ugi tetrazole multicomponent reaction
allows the synthesis of a novel macrocyclic cyclen deriva-
tive with four appendant tetrazole arms in just two steps
in excellent yields. This ligand, called TEMDO, turns out to
have a high complexation affinity with lanthanoid metals.
Here we describe the design, synthesis, solid-state struc-
ture, binding constant, and some MRI applications of the
Gd-TEMDO complex as the first example of a congeneric
family of oligo-amino tetrazoles.
Since its discovery in 1971, magnetic resonance imaging (MRI)
has evolved into a major medical imaging technique and has
rapidly found its way into daily clinical diagnostics.[1] Today,
more than 20000 MRI scanners are operating in hospitals
worldwide and more than 50 million clinical MRI examinations
are performed every year. The impact of this breakthrough
technology for mankind was honored by the Nobel Prize in
Physiology or Medicine in 2003.[2] As opposed to other imaging
techniques, MRI is a radiation-less method and is widely used
in medical diagnosis and staging of disease. Although MRI
does not, in principle, require contrast agents, their use dra-
matically accelerates acquisition times and signal intensity. MRI
contrast agents work by accelerating the relaxation of water
protons in the surrounding tissues. Paramagnetic ions are suit-
Scheme 1. DOTA, general formula of oligo-amino tetrazoles, TEMDO, and
retro synthesis thereof. Pg=benzyl, tert-octyl. b-cyanoethyl.
dodecane (TEMDO, 3, see Scheme 1). We describe the design,
synthesis, solid state structure, binding constant, and some
MRI applications of the Gd-TEMDO complex.
The tetrazole is a known bioisostere of the carboxylic acid
with often superior PKPD properties.[5] For example, the tetra-
zolate allows for a wider delocalization of the negative charge
and could thus facilitate better penetration into tissue. In the
context of MRI, a tetrazolate ligand could also help to increase
proton relaxivity through changes in the metalÀH distance by
electron delocalization towards the ligand. Moreover, through
subtle changes in the ligand composition and geometry even-
tually higher tilt angles between the plane of the bound water
and the metalÀO bond could be induced by hydrogen bond-
ing of the coordinated water to an appropriate side group of
the chelate, which could result in a significant decrease of the
metal–proton distance. Thus, we reasoned that oligoamino tet-
razoles are suitable for MRI, exhibiting different and potentially
better physicochemical and biological properties compared to
their carboxylic acid analogues. Surprisingly, oligoamino tetra-
zoles in general and specifically as MRI agents are unknown.[6]
Based on our longstanding expertise in multicomponent reac-
tion (MCR) chemistry and its versatility, speed and ease-to-per-
form, we choose MCR as a perfect tool to assemble this func-
tional material class of MRI agents.[7] As a first synthetic target
of the class of the oligoamino tetrazoles (2), we chose the tet-
razole analogue (3) of DOTA[8] (1) (Scheme 1).
able contrast agents and, amongst them, gadolinium (Gd3+
)
complexes are by far the most widely used MRI contrast
agents, owing to their seven unpaired electrons, slow electron-
ic relaxation, and excellent complex stability. Although clinical-
ly approved MRI contrast agents are generally considered to
be safe, a small number of fatalities were reported likely due
to nephron- and neurotoxicity by Gd-leakage.[3] In addition,
not only patients with pre-existing renal failure are affected by
Gd-leakage, but also patients with other conditions showed
considerable neuronal tissue concentrations of Gd3+ after
being subjected to Gd-based contrast agents (GBCAs).[4]
Here, we introduce the first example of the novel class of oli-
goamino tetrazoles as chelating agents useful in imaging:
1,4,7,10-tetrakis((1H-tetrazol-5-yl)methyl)-1,4,7,10-tetraazacyclo-
[a] A. Boltjes,+ Dr. A. Shrinidhi,+ Prof. Dr. A. Dçmling
Department of Drug Design
Groningen Research Institute of Pharmacy, University of Groningen
A. Deusinglaan 1, Groningen (The Netherlands)
E-mail: a.s.s.domling@rug.nl
In our retrosynthesis, we envisioned that TEMDO can be fast
and convergently synthesized by applying an Ugi tetrazole re-
action from available cyclen.[9] The unprotected TEMDO ligand
suitable for metal complexation has to be generated by cleav-
age of the isocyanide substituent. In principle, several cleava-
ble isocyanides such as Walborsky’s, benzyl-, or tert-butyl are
suitable; however, we have chosen b-cyanoethyl isocyanide 4
here, owing to its mild cleavage conditions.
[b] K. van de Kolk
Central Animal Facility
University of Groningen/UMCG
A. Deusinglaan 50 (The Netherlands)
[c] Dr. E. Herdtweck
Institut für Anorganische Chemie
Technische Universität München
Lichtenbergstrasse 4, 85747 Garching bei München (Germany)
[+] These authors contributed equally to this work.
In fact, after some optimization of the reaction conditions
we could obtain the Ugi tetrazole product 8 in quantitative
yields by reacting the commercially available starting materials
cyclen 5, paraformaldehyde 6, and TMS azide 7, as a safe hy-
[**] TEMDO=1,4,7,10-tetrakis((1H-tetrazol-5-yl)methyl)-1,4,7,10-tetraazacyclo-
dodecane.
Supporting information for this article is available on the WWW under
Chem. Eur. J. 2016, 22, 7352 – 7356
7353
ꢀ 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim