Sarcophagine chelation
Sarcophagine is a cage-shaped molecule that locks copper atoms inside so tightly that the copper cannot escape once the imaging or treatment dose is made, even inside the body.
Overview
Sarcophagine ('sar', 3,6,10,13,16,19-hexaazabicyclo[6.6.6]icosane) is a hexaazamacrobicyclic cage-amine ligand, developed originally by Sargeson and colleagues, whose fully encapsulating three-dimensional cage confers exceptional kinetic inertness on its copper(II) complexes. Because the copper ion is enclosed rather than merely chelated at a macrocycle rim, sarcophagine complexes form rapidly (typically 5-20 minutes) at room temperature across a broad pH range (4-9) and resist demetalation and reduction to Cu+ far more effectively than open-chain or single-ring chelators such as DTPA or NOTA. The bifunctional derivative MeCOSar (methyl-carboxylate sarcophagine) is the most widely used variant for peptide and antibody conjugation.
Sarcophagine chelation is the basis of the clinical 64Cu/67Cu-SARTATE and 64Cu/67Cu-SAR-bisPSMA agents and of numerous 64Cu-labelled antibody constructs (including sarcophagine-trastuzumab and sarcophagine-cetuximab conjugates for PET imaging), where head-to-head comparisons have shown less than 6% loss of 64Cu from sarcophagine-antibody conjugates in serum over 48 hours, matching or beating NOTA. A drawback of first-generation sarcophagines (SarAr) is that the residual positive charge on the copper-cage complex increases kidney retention of labelled antibody fragments; charge-modified analogues (AmBaSar, and dibromomaleimide-linked variants) reduce this off-target renal uptake while retaining the fast, room-temperature labelling that makes sarcophagines attractive for 64Cu (and increasingly 67Cu) theranostic pairs.
How it works
A three-dimensional hexaazamacrobicyclic cage fully encloses a copper ion on all sides, rather than gripping it at a ring rim, so the metal cannot demetalate or be reduced away in vivo; the closed cage also lets complexation happen in minutes at room temperature across a wide pH range.
Dependencies
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Latest papers
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