Mono- and bis-maleimido-functionalized NOTA for site-specific modifications


Mono- and bis-maleimido-functionalized NOTA for site-specific modifications

Förster, C.; Schubert, M.; Pietzsch, H.-J.; Steinbach, J.

Objectives:

The purpose was to develop applicable synthetic strategies for the preparation of new NOTAmaleimides for site-specific introduction into radiopharmaceutically relevant (macro)molecules. This approach should be characterized by low synthetic effort and high grade of flexibility concerning length and chemical nature of spacer units connecting the NOTA to the maleimide entities.
Methods:
To translate the idea and above stated requirements, the commercially available 1 and 2 were used as starting NOTA compounds. For the covalent attachment of maleimide derivatives with different linkers (aliphatic C2 to C6 as well as PEG28), two synthetic pathways were investigated (scheme 1). The first is based on nucleophilic addition reaction of an aromatic isothiocyanate with a primary amino group. Due to the limited availability of amino functionalized maleimides, a second protocol was developed. Therefore, the aromatic amino group of 2 was used for coupling reactions with NHS-ester functionalized maleimide derivatives. After establishment of these two
methods, a selection of products was engaged in coupling reactions with thiol modified L-oligonucleotides (L-DNA) for tumor pretargeting studies.

Results:

The high sensitivity of the starting materials as well as the products 3a-b and 4a-e in terms of hydrolyzation side reactions necessitated optimization of reaction parameters (solvent, pH value, stoichiometry, reaction time, etc.). Yields of 30-40 % and 83-86 % for 3a-b and 4a-d were achieved, respectively. A yield of 50 % was attained for the PEG28 derivative 4e. High specific activities resulted upon labeling different L-DNA-NOTA conjugates with 64Cu and 68Ga for biodistribution studies in Wistar rats.
Conclusions:
As a proof of concept, we demonstrate the practicability of these two methods by engaging various linkers. The broad variety of commercially available NHS-ester modified maleimides in respect to different spacer length, shape, and polarity emphasizes the high flexibility for the design of tailored NOTA-maleimides for diverse applications.

  • Poster
    19th International Symposium on Radiopharmaceutical Sciences, 28.08.-02.09.2011, Amsterdam, The Netherlands
  • Abstract in refereed journal
    Journal of Labelled Compounds and Radiopharmaceuticals 54(2011), S324
    ISSN: 0362-4803

Permalink: https://www.hzdr.de/publications/Publ-16059
Publ.-Id: 16059