# Sarcophagine chelation

Source: https://nuclide.cc/technologies/sarcophagine-chelation/  
Nuclide record `sarcophagine-chelation` (Technology). Data CC BY-NC 4.0, attribute "Data from Nuclide (nuclide.cc)"; commercial use needs a licence.

## TL;DR

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.

## Summary

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.

## Fields

- Kind: Technology
- Last checked: 2026-09-22
- Also known as: Sar; cage amine chelator; MeCOSar
- Tags: chemistry; chelator; copper-64
- Principle: 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.
- Since: 1980s (cage-amine ligand chemistry by Sargeson); bifunctional MeCOSar-NHS for bioconjugation from mid-2000s

## Sources

- Development of multi-functional chelators based on sarcophagine for 64Cu chelation (PMC): https://pmc.ncbi.nlm.nih.gov/articles/PMC6270798/
- Comparison of bifunctional chelators including sarcophagine for 64Cu-rituximab labelling (PMC): https://pmc.ncbi.nlm.nih.gov/articles/PMC4756438/
- Potential theranostics of breast cancer with copper-64/67-sarcophagine-trastuzumab (Chem. Sci. 2025): https://pubs.rsc.org/en/content/articlehtml/2025/sc/d4sc06969b
- IAEA: Copper-64 radiopharmaceuticals - production, quality control and clinical applications: https://www-pub.iaea.org/MTCD/Publications/PDF/PUB1961_web.pdf

## Connected records

- technologies: [Cyclotron isotope production (F-18, Ga-68, Cu-64, Zr-89, At-211)](https://nuclide.cc/technologies/cyclotron-isotope-production/), [DOTA chelation](https://nuclide.cc/technologies/dota-chelation/), [Pretargeted radioimmunotherapy](https://nuclide.cc/technologies/pretargeted-radioimmunotherapy/), [Radio-antibody & radio-ADC](https://nuclide.cc/technologies/radioimmunotherapy/)
- isotopes: [Copper-64](https://nuclide.cc/isotopes/cu-64/), [Copper-67](https://nuclide.cc/isotopes/cu-67/)

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