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Metal Chelating Oligonucleotides Synthesis and Conjugation

Chelator-modified and metal-mediated oligonucleotides for radiometal labeling, lanthanide imaging, MRI contrast, and His-tag capture. Options include DOTA, DTPA, NOTA, EDTA, NTA linkers and bipyridine/terpyridine/phenanthroline base ligands. Complete design → synthesis → purification/QC → RUO→GMP-like documentation.

DOTA / NOTA / DTPA EDTA / NTA Lanthanides / Radiometals MRI (Gd³⁺) Ni²⁺-NTA Capture RUO → GMP-like
Overview Products Workflow Technical Notes FAQ Speak to a Scientist

Custom Oligo Synthesis for Metal Chelation

Bio‑Synthesis, Inc. designs and manufactures metal‑chelating oligonucleotides for radiometal (e.g., 64Cu, 68Ga, 111In), lanthanide/TR‑FRET, MRI (Gd³⁺), and Ni²⁺‑NTA His‑tag capture applications. We offer terminal chelator linkers (DOTA, NOTA, DTPA, EDTA, NTA) and metal‑ligand base analogs (bipyridine, terpyridine, phenanthroline), delivered with ISO‑aligned QC (HPLC/UPLC, LC‑MS, metal‑loading checks) and RUO → GMP‑like documentation. Our Lewisville, Texas team supports end‑to‑end workflows—application‑led design, synthesis, purification, verified metal complexation, and tech transfer for scale‑up.

Formats
Tubes • Plates • Kitting
Scale
µmol → multi‑gram
QC
UPLC/HPLC • LC-MS •
Metal loading
Supply
RUO → GMP‑like
What we manufacture
  • Chelator linkers: DOTA, DTPA, NOTA, EDTA, NTA (5′/3′ or internal via amino/azide/alkyne handles).
  • Metal-ligand bases: Bipyridine, terpyridine, phenanthroline derivatives.
  • Custom panels: Multiplex probe sets for radiolabeling, TR-FRET, or capture assays.
Services you can expect
  • Application-led design: isotope/metal match, spacer geometry, site selection.
  • Process & purification: desalt/HPLC/PAGE, controlled drying, verified metal loading.
  • Documentation: ISO-aligned CoA, sequence map, loading/chelating conditions.
  • Scale-up & transfer: RUO → GMP-like pathways with phased tech transfer.

Products

Product Description Function Code
DOTA-Oligo Macrocyclic chelator for strong Cu²⁺/Ga³⁺/Gd³⁺ coordination; ideal for PET/MRI labeling and stable metal retention. Radiometal / MRI [DOTA]
NOTA-Oligo Compact macrocycle optimized for Ga³⁺; fast complexation and high in-vivo stability. PET / Radiometal [NOTA]
DTPA-Oligo Acyclic chelator for In³⁺/Gd³⁺; widely used in SPECT/MRI and lanthanide tagging. SPECT / MRI [DTPA]
EDTA-Oligo Versatile aminopolycarboxylate chelator for general metal coordination, scavenging, and capture workflows. General Chelation [EDTA]
NTA-Linker (Ni²⁺) Ni²⁺–NTA motif enabling His-tag capture or surface immobilization; available 5′/internal with spacers. Affinity Capture [NTA]
Bipyridine-Base 2,2′-Bipyridine ligand as an internal base analog for metal-mediated pairing or electron-transfer constructs. Metal-Mediated Base [Bpy]
Terpyridine-Base Terpyridine motif for multidentate coordination inside duplex regions; useful in nanostructures. Metal-Mediated Base [Terpy]
Phenanthroline-Base Phenanthroline ligand for Cu²⁺/Ru²⁺ binding; electrochemical and photophysical applications. Metal-Mediated Base [Phen]
Technical Notes
Metal Selection & Complexation
  • Isotope/Application fit: Cu-64/67 (PET/therapy), Ga-68 (rapid PET), In-111 (SPECT), Gd³⁺ (MRI), Eu³⁺/Tb³⁺ (TR-FRET).
  • pH & buffer: Complex at ≤ pH 6.5–7.0 for Ga³⁺/In³⁺; avoid phosphate for some metals (precipitation risk).
  • Order of operations: Label chelator first, then couple to partners/surfaces to reduce metal loss.
  • Verify loading: LC-MS (mass shift), ICP-MS, or lanthanide UV/fluorescence.
Placement & Spacers
  • Terminal vs internal: Prefer 5′/3′ for bulky macrocycles (DOTA/DTPA/NOTA) with TEG/PEG spacers.
  • Internal ligands: Use bipyridine/terpyridine/phenanthroline bases for proximity-driven effects or nanodesign.
  • Multiplex capture: Array NTA units for stronger His-tag binding; release with imidazole/EDTA.
Buffers, Compatibility & Stability
  • Avoid chelator contaminants (free EDTA, high phosphate) during labeling; use acetate/MES/HEPES as compatible.
  • Protect Cu²⁺ constructs from strong reductants; consider antioxidant conditions as needed.
  • For Gd³⁺ constructs, quantify free Gd; perform challenge tests (Zn²⁺, Ca²⁺).
QC & Safety
  • Purification: HPLC/PAGE; identity by LC-MS; confirm chelate loading (ICP-MS/radioactivity).
  • Document specific activity for radiolabeled oligos and residual free metal.
  • Follow isotope safety, shielding, and waste controls.

Workflow — Label → Purify → Validate → Apply

  1. Choose chelator & metal: Target isotope/lanthanide and application.
  2. Conjugate chelator: Attach 5′/3′ or internal via amino/azide/alkyne handles.
  3. Metal loading: Label under recommended pH, then quench/exchange as required.
  4. Purify & QC: HPLC/PAGE; confirm loading (LC-MS/ICP-MS) and stability.
  5. Use & store: Follow buffer/storage guidance and document specific activity.
  • Applications: PET/SPECT/MRI probes, TR-FRET readouts, His-tag capture/immobilization.
  • Combinations: Pair with LNA/ZNA for affinity, or dyes/biotin for multimodal assays.
  • Kitting: Plates/tubes with barcodes, concentration/aliquoting per protocol.
Need help choosing the right chelator & metal?
Tell us your target (PET/SPECT, pull-downs, luminescence) and QC requirements—we’ll design the optimal linkage and coupling chemistry.

FAQ

Is metal chelation a type of modification or a function?
It is a modification type (chelator addition). Its functions include radiometal/lanthanide labeling, MRI contrast, and affinity capture.
Which chelator should I pick—DOTA, NOTA, DTPA, EDTA, or NTA?
DOTA/NOTA for PET/MRI (Cu/Ga/Gd), DTPA for In/Gd and lanthanides, EDTA for general chelation/scavenging, NTA for Ni²⁺–His capture. Match metal, kinetics, and stability.
Can I combine chelation with other modifications?
Yes. Pair with LNA/ZNA for affinity, dyes/biotin for detection/capture, or PEG/TEG spacers to mitigate sterics and improve solubility.
Do you offer GMP-grade manufacturing?
We provide ISO-aligned workflows with phase-appropriate QC and RUO→GMP-like documentation. For GMP programs, we can scope enhanced documentation and tech transfer packages.

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References — Metal-Chelator Oligonucleotide Modifications

EDTA / Phenanthroline (Chemical Nucleases) Terpyridine / Bipyridine Complexes DOTA / NOTA / DTPA (Radiometals) NTA (Ni²⁺–His-tag Capture) Lanthanide Chelates (Luminescence)
EDTA / Phenanthroline (Chemical Nucleases)
  1. François JC, Saison-Behmoaras E, Chassignol M, et al. Sequence-specific recognition and cleavage of duplex DNA via triple-helix formation by oligonucleotides covalently linked to a phenanthroline-copper chelate. PNAS. 1989;86:9702-9706. PubMed
  2. Chen CHB, Sigman DS. Sequence-specific scission of RNA by 1,10-phenanthroline-copper linked to deoxyoligonucleotides. J Am Chem Soc. 1988;110:6570-6572. ACS
  3. Van Dyke MW, Dervan PB. Methidiumpropyl-EDTA·Fe(II) and DNase I footprinting on fragments containing multiple binding sites. Nucleic Acids Res. 1983;11:5555-5571. PMC
  4. Bowen WS, Winnik MA, Dervan PB, et al. Comparison of rRNA cleavage by tethered 1,10-phenanthroline-Cu(II) and EDTA-Fe(II) complexes. Nucleic Acids Res. 2001;29:1664-1675. PubMed
  5. Tullius TD, Greenbaum JA. Mapping nucleic acid structure by hydroxyl radical cleavage. Curr Opin Chem Biol. 2005;9:127-134. Elsevier
  6. Chapman JR, et al. Systematic Fe(II)-EDTA method of dose-dependent hydroxyl radical generation. Anal Chem. 2023;95:14135-14143. ACS
Terpyridine / Bipyridine Complexes
  1. Inoue H, et al. Efficient site-specific cleavage of RNA using a terpyridine·Cu(II) complex tethered to antisense oligonucleotides. Chem Commun. 1999:1445-1446. RSC
  2. Trawick BN, et al. Enhancing sequence-specific RNA cleavage with Cu(II)–serinol–terpyridine oligonucleotide conjugates. Bioconjug Chem. 2001;12:900-905. ACS
  3. Sakamoto S, et al. Highly efficient catalytic RNA cleavage by the cooperative action of two Cu(II) complexes embodied within an antisense oligonucleotide. Nucleic Acids Res. 2003;31:1416-1426. PMC
  4. Erxleben A. Review: Interactions of copper complexes with nucleic acids (incl. tpy systems). Coord Chem Rev. 2018;363:88-108. Elsevier
  5. Kainat SF, et al. Recent developments in the synthesis and applications of terpyridine ligands and complexes. RSC Adv. 2024;14:—. RSC
DOTA / NOTA / DTPA (Radiometal-Labeled Oligos & Aptamers)
  1. Roivainen A, et al. 68Ga-labeled oligonucleotides for in vivo PET imaging. J Nucl Med. 2004;45:347-355. JNM
  2. Rockey WM, et al. Synthesis and radiolabeling of chelator–RNA aptamer conjugates (64Cu; NOTA/DOTA). Bioorg Med Chem. 2011;19:4080-4090. Elsevier
  3. Kang L, et al. 64Cu-NOTA A10 aptamer: preparation and stability. J Vis Exp. 2019;(147):e58716. PubMed
  4. Li P, et al. Preliminary evaluation of 64Cu-NOTA-AS1411 DNA aptamer as a PET tracer. J Radioanal Nucl Chem. 2023;—. Springer
  5. Si Z, et al. Exploration of 68Ga-DOTA-MAL as a versatile vehicle for biomolecule labeling. ACS Omega. 2023;8:—. ACS
  6. Liu D, et al. Radiolabeling of functional oligonucleotides for molecular imaging (review). Front Oncol. 2022;12:913079. PMC
  7. Edelmann MR, et al. A brief review of radiolabelling nucleic acid–based ligands. J Label Compd Radiopharm. 2024;67:—. Wiley
NTA (Ni2+–His-tag Capture) & NTA-Oligo Conjugates
  1. Bio-Synthesis, Inc. Nitrilotriacetate (NTA) Oligo Conjugates. Product/tech note. Lewisville, TX. biosyn.com
  2. Knecht S, et al. Oligohis-tags: mechanisms of binding to Ni2+–NTA surfaces. J Mol Recognit. 2009;22:270-279. PubMed
  3. Raghunath G, et al. Kinetics of histidine-tagged protein association to Ni-NTA (stopped-flow). Biophys J. 2019;117:—. PMC
  4. Zhu L, et al. Biosensors based on NTA–metal complex binding events (review). Biosensors. 2023;13:384. PMC
Lanthanide Chelates (Luminescent Probes; DTPA/NOTA/HOPO families)
  1. Heffern MC, et al. Lanthanide probes for bioresponsive imaging (overview). Chem Rev. 2013;113:—. PMC
  2. Cho U, et al. Lanthanide-based optical probes of biological systems (design & applications). Int J Mol Sci. 2020;21:—. PMC
  3. Martinon TLM, et al. Luminescent lanthanide probes for phosphate detection & nucleic acids. Chem Asian J. 2022;17:e202200495. Wiley
  4. Alexander C, et al. Luminescent lanthanides in biorelated applications (from molecules to nanoparticles). Chem Rev. 2025;—. Preprint/PDF
  5. Selvin PR. Progress in lanthanides as luminescent probes (includes DTPA scaffolds). Annu Rev Biophys Biomol Struct. 2002;31:—. PDF
  6. Couchet JM, et al. Eu(III) and Tb(III) systems derived from DTPA: luminescent complexes & bio-apps. J Lumin. 2011;131:—. Elsevier
  7. Krasnoperov LN, et al. Luminescent lanthanide probes for ultrasensitive nucleic-acid detection. Anal Biochem. 2010;397:—. PMC

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