Labeling biomolecules with radiorhenium: a review of the bifunctional chelators

Abstract

For radiotherapy, biomolecules such as intact antibodies, antibody fragments, peptides, DNAs and other oligomers have all been labeled with radiorhenium ((186)Re and (188)Re). Three different approaches have been employed that may be referred to as direct, indirect and integral labeling. Direct labeling applies to proteins and involves the initial reduction of endogenous disulfide bridges to provide chelation sites. Indirect labeling can apply to most biomolecules and involves the initial attachment of an exogenous chelator. Finally, integral labeling is a special case applying only to small molecules in which the metallic radionuclide serves to link two parts of a biomolecule together in forming the labeled complex. While the number of varieties for the direct and integral radiolabeling approaches is rather limited, a fairly large and diverse number of chelators have been reported in the case of indirect labeling. Our objective herein is to provide an overview of the various chelators that have been used in the indirect labeling of biomolecules with radiorhenium, including details on the labeling procedures, the stability of the radiolabel and, where possible, the influence of the label on biological properties.

Fig. (1)

General structures, from left to right, of the ReO-N₃S, ReO-N₂S₂, X₄Re=N-NH-(hynic), and Re(CO)₃-tridentate complexes shown attached to a biomolecule.

Fig. (2)

Preconjugation radiolabeling of antibody (Ab) using MAG₂-GABA

Fig. (3)

Preconjugation radiolabeling of antibody (Ab) using S-benzoyl-MAG₃

Fig. (4)

Preconjugation radiolabeling of antibody (Ab) using MAGIPG

Fig. (5)

Postconjugation radiolabeling of a S-benzoyl-MAG₃ conjugated model molecule

Fig. (6)

The expected reactions involved in the postconjugation rhenium labeling of a MORF oligomer with S-acetyl NHS-MAG₃ as bifunctional chelator

Fig. (7)

Postconjugation ¹⁸⁸Re labeling of a peptide (P829)

Fig. (8)

Non-radioactive rhenium labeling of TAT synthesized with a C terminal N₃S chelator

Fig. (9)

Labeling with ¹⁸⁸Re of the AG 8.0 peptide synthesized with a N terminal N₃S chelator

Fig. (10)

Examples of novel N₃S chelators potentially for rhenium labeling of biomolecules.

Fig. (11)

Rhenium labeling of a C5-N₂S₂ conjugated antibody (Ab)

Fig. (12)

Proposed conjugation and labeling of an antibody (Ab) using a N₂S₄ chelator (EDTM)

Fig. (13)

The ¹⁸⁸Re Labeling of the IMP-192 peptide bearing a N₂S₂ chelator

Fig. (14)

Labeling of ethylene dicysteine (EC) with radiorhenium

Fig. (15)

Labeling of alkyl chains using a N₂S₂ chelator

Fig. (16)

Postconjugation ¹⁸⁸Re radiolabeling of P₂S₂-peptide by citrate transchelation

Fig. (17)

Postconjugation ¹⁸⁸Re radiolabeling of N₂P₂-BFCA by transchelation

Fig. (18)

The structure of trisuccin-antibody (Ab) conjugate