Abstract
The field of targeted radionuclide therapy is rapidly growing, highlighting the need for wider radionuclide availability. Soft Lewis acid ions, such as radioisotopes of platinum, rhodium and palladium, are particularly underdeveloped. This is due in part to a lack of compatible bifunctional chelators. These allow for the practical bioconjugation to targeting vectors, in turn enabling radiolabeling. The [16]andS4 macrocycle has been reported to chelate a number of relevant soft metal ions. In this work, we present a procedure for synthesizing [16]andS4 in 45% yield (five steps, 12% overall yield), together with a selection of strategies for preparing bifunctional derivatives. An ester-linked N-hydroxysuccimide ester (NHS, seven steps, 4% overall yield), an ether-linked isothiocyanate (NCS, eight steps, 5% overall yield) and an azide derivative were prepared. In addition, a new route to a carbon-carbon linked carboxylic acid functionalized derivative is presented. Finally, a general method for conjugating the NHS and NCS derivatives to a polar peptide (octreotide) is presented, by dissolution in water:acetonitrile (1:1), buffered to pH 9.4 using borate. The reported compounds will be readily applicable in radiopharmaceutical chemistry, by facilitating the labeling of a range of molecules, including peptides, with relevant soft radiometal ions.
Highlights
The field of nuclear medicine has seen remarkable growth in recent years, in particular within oncology
We present a procedure for synthesizing [16]andS4 in 45% yield, together with a selection of strategies for preparing bifunctional derivatives
To broaden the application of the new macrocyclic chelator derivatives, three different linker types were prepared (Figure 1B, bottom), all with the potential to further the use of soft radiometals in nuclear medicine
Summary
The field of nuclear medicine has seen remarkable growth in recent years, in particular within oncology. Radiopharmaceuticals are typically constructed as conjugates of receptor-specific vectors with radionuclides This requires the use of chelators, capable of trapping the radiometal ions as stable complexes (Figure 1A). Bifunctional [16]aneS [16]aneS44 chelators chelators as as aa general general strategy strategy for for soft soft radiometal radiometal complexes complexes for for bio-conjugation, bio-conjugation, with with application in targeted radiotherapy and radiodiagnostics. These soft radiometals have a Radiometals that form soft Lewis acid cations are available These soft radiometals high binding affinity to sulfur-containing ligands (vide supra). [16]aneS4 belongs to a larger class cane) as a potential chelator fortransition late transition radiometals.
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