Issue 42, 2017

Preparation of tetrazine-containing [2 + 1] complexes of 99mTc and in vivo targeting using bioorthogonal inverse electron demand Diels–Alder chemistry

Abstract

The aim of this work was to synthesize and evaluate [2 + 1] 99mTc(I) polypyridine complexes containing tetrazines, which along with the corresponding Re(I) complexes, represent a new class of isostructural nuclear and turn-on luminescent probes that can be derivatized and targeted using bioorthogonal chemistry. To this end, [2 + 1] complexes of 99mTc(I) of the type [99mTc(CO)3(N^N)(L)] (N^N = bathophenanthroline disulfonate (BPS) or 2,2′-bipyridine (bipy)), where the monodentate ligand (L) was a tetrazine linked to the metal through an imidazole derivative, were prepared. The desired products were obtained in nearly quantitative radiochemical yield by adding [99mTc(CO)3(N^N)(OH2)]n to the imidazole-tetrazine ligand and heating at 60 °C for 30 min. Measurement of the reaction kinetics between the tetrazine and (E)-cyclooct-4-enol revealed a second-order rate constant of 8.6 × 103 M−1 s−1 at 37 °C, which is suitable for in vivo applications that require rapid coupling. Stability studies showed that the metal complexes were resistant to ligand challenge and exhibited reasonable protein binding in vitro. Biodistribution studies of the more water-soluble BPS derivative in normal mice, one hour after administration of a bisphosphonate derivative of trans-cyclooctene (TCO-BP), revealed high activity concentrations in the knee (9.3 ± 0.3 %ID g−1) and shoulder (5.3 ± 0.7 %ID g−1). Using the same pretargeting approach, SPECT/CT imaging showed that the [2 + 1] tetrazine complex localized to implanted skeletal tumors. This is the first report of the preparation of 99mTc complexes of BPS and demonstration that their tetrazine derivatives can be used to prepare targeted imaging probes by employing bioorthogonal chemistry.

Graphical abstract: Preparation of tetrazine-containing [2 + 1] complexes of 99mTc and in vivo targeting using bioorthogonal inverse electron demand Diels–Alder chemistry

Supplementary files

Article information

Article type
Paper
Submitted
25 Eph 2017
Accepted
14 Jun 2017
First published
15 Jun 2017

Dalton Trans., 2017,46, 14691-14699

Preparation of tetrazine-containing [2 + 1] complexes of 99mTc and in vivo targeting using bioorthogonal inverse electron demand Diels–Alder chemistry

A. Yazdani, N. Janzen, S. Czorny, R. G. Ungard, T. Miladinovic, G. Singh and J. F. Valliant, Dalton Trans., 2017, 46, 14691 DOI: 10.1039/C7DT01497J

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