Novel Bifunctional [16]aneS4-Derived Chelators for Soft Radiometals

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.

Keywords: bifunctional chelators; bio-conjugation; radiation therapy; sulfur containing macrocycles.

Figure 1

(A) Bifunctional [16]aneS₄ chelators as a general strategy for soft radiometal complexes for bio-conjugation, with application in targeted radiotherapy and radiodiagnostics. (B) Examples of reported [16]aneS₄ chelator derivatives and the novel [16]aneS₄ bifunctional chelators reported in this manuscript.

Figure 2

Synthesis of [16]aneS₄-ol (see SI for further details).

Figure 3

Synthesis of bifunctional [16]aneS4 chelator derivatives, including the NHS ester, isothiocyanate and azide derivative.

Figure 4

Alternative synthesis of bifunctional [16]aneS4 chelator.

Figure 5

Bioconjugation of 9 and 13 with octreotide (hypothetical selective N-terminal functionalization shown for clarity).