Functionally Versatile and Highly Stable Chelator for 111 In and 177 Lu: Proof-of-Principle Prostate-Specific Membrane Antigen Targeting

Bioconjug Chem. 2019 May 15;30(5):1539-1553. doi: 10.1021/acs.bioconjchem.9b00225. Epub 2019 May 5.


Here, we present the synthesis and characterization of a new potentially nonadentate chelator H4pypa and its bifunctional analogue tBu4pypa-C7-NHS conjugated to prostate-specific membrane antigen (PSMA)-targeting peptidomimetic (Glu-urea-Lys). H4pypa is very functionally versatile and biologically stable. Compared to the conventional chelators (e.g., DOTA, DTPA), H4pypa has outstanding affinities for both 111In (EC, t1/2 ≈ 2.8 days) and 177Lu (β-,γ, t1/2 ≈ 6.64 days). Its radiolabeled complexes were achieved at >98% radiochemical yield, RT within 10 min, at a ligand concentration as low as 10-6 M, with excellent stability in human serum over at least 5-7 days (<1% transchelation). The thermodynamic stabilities of the [M(pypa)]- complexes (M3+ = In3+, Lu3+, La3+) were dependent on the ionic radii, where the smaller In3+ has the highest pM value (30.5), followed by Lu3+ (22.6) and La3+ (19.9). All pM values are remarkably higher than those with DOTA, DTPA, H4octapa, H4octox, and H4neunpa. Moreover, the facile and versatile bifunctionalization enabled by the p-OH group in the central pyridyl bridge of the pypa scaffold (compound 14) allows incorporation of a variety of linkers for bioconjugation through easy nucleophilic substitution. In this work, an alkyl linker was selected to couple H4pypa to a PSMA-targeting pharmacophore, proving that the bioconjugation sacrifices neither the tumor-targeting nor the chelation properties. The biodistribution profiles of 111In- and 177Lu-labeled tracers are different, but promising, with the 177Lu analogue particularly outstanding.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antigens, Surface / chemistry*
  • Chelating Agents / chemistry*
  • Glutamate Carboxypeptidase II / chemistry*
  • Humans
  • Indium Radioisotopes / chemistry*
  • Lutetium / chemistry*
  • Male
  • Proof of Concept Study
  • Prostate / metabolism
  • Radiopharmaceuticals / chemistry


  • Antigens, Surface
  • Chelating Agents
  • Indium Radioisotopes
  • Radiopharmaceuticals
  • Lutetium
  • FOLH1 protein, human
  • Glutamate Carboxypeptidase II