Multivalent bifunctional chelator scaffolds for gallium-68 based positron emission tomography imaging probe design: Signal amplification via multivalency

Ajay N. Singh, Wei Liu, Guiyang Hao, Amit Kumar, Anjali Gupta, Orhan K. Öz, Jer Tsong Hsieh, Xiankai Sun

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43 Scopus citations


The role of the multivalent effect has been well recognized in the design of molecular imaging probes toward the desired imaging signal amplification. Recently, we reported a bifunctional chelator (BFC) scaffold design, which provides a simple and versatile approach to impart multivalency to radiometal based nuclear imaging probes. In this work, we report a series of BFC scaffolds (tBu3-1-COOH, tBu3-2-(COOH) 2, and tBu3-3-(COOH)3) constructed on the framework of 1,4,7-triazacyclononane-1,4,7-triacetic acid (NOTA) for 68Ga-based PET probe design and signal amplification via the multivalent effect. For proof of principle, a known integrin αvβ3 specific ligand (c(RGDyK)) was used to build the corresponding NOTA conjugates (H31, H32, and H33), which present 1-3 copies of c(RGDyK) peptide, respectively, in a systematic manner. Using the integrin αvβ3 binding affinities (IC50 values), enhanced specific binding was observed for multivalent conjugates (H32: 43.9 ± 16.1 nM; H33: 14.7 ± 5.0 nM) as compared to their monovalent counterpart (H31: 171 ± 60 nM) and the intact c(RGDyK) peptide (204 ± 76 nM). The obtained conjugates were efficiently labeled with 68Ga3+ within 30 min at room temperature in high radiochemical yields (>95%). The in vivo evaluation of the labeled conjugates, 68Ga-1, 68Ga-2, and 68Ga-3, was performed using male severe combined immunodeficiency (SCID) mice bearing integrin αvβ3 positive PC-3 tumor xenografts (n = 3). All 68Ga-labeled conjugates showed high in vivo stability with no detectable metabolites found by radio-HPLC within 2 h postinjection (p.i.). The PET signal amplification in PC-3 tumor by the multivalent effect was clearly displayed by the tumor uptake of the 68Ga-labeled conjugates ( 68Ga-3: 2.55 ± 0.50%ID/g; 68Ga-2: 1.90 ± 0.10%ID/g; 68Ga-1: 1.66 ± 0.15%ID/g) at 2 h p.i. In summary, we have designed and synthesized a series of NOTA-based BFC scaffolds with signal amplification properties, which may find potential applications as diagnostic gallium radiopharmaceuticals.

Original languageEnglish (US)
Pages (from-to)1650-1662
Number of pages13
JournalBioconjugate Chemistry
Issue number8
StatePublished - Aug 17 2011

ASJC Scopus subject areas

  • Biotechnology
  • Bioengineering
  • Biomedical Engineering
  • Pharmacology
  • Pharmaceutical Science
  • Organic Chemistry


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