[52Mn]Mn-BPPA-Trastuzumab: A Promising HER2-Specific PET Radiotracer

J Med Chem. 2024 May 23;67(10):8261-8270. doi: 10.1021/acs.jmedchem.4c00344. Epub 2024 May 1.

Abstract

This study aimed to develop a novel radiotracer using trastuzumab and the long-lived [52Mn]Mn isotope for HER2-targeted therapy selection and monitoring. A new Mn(II) chelator, BPPA, synthesized from a rigid bispyclen platform possessing a picolinate pendant arm, formed a stable and inert Mn(II) complex with favorable relaxation properties. BPPA was converted into a bifunctional chelator (BFC), conjugated to trastuzumab, and labeled with [52Mn]Mn isotope. In comparison to DOTA-GA-trastuzumab, the BPPA-trastuzumab conjugate exhibits a labeling efficiency with [52Mn]Mn approximately 2 orders of magnitude higher. In female CB17 SCID mice bearing 4T1 (HER2-) and MDA-MB-HER2+ (HER2+) xenografts, [52Mn]Mn-BPPA-trastuzumab demonstrated superior uptake in HER2+ cells on day 3, with a 3-4 fold difference observed on day 7. Overall, the hexadentate BPPA chelator proves to be exceptional in binding Mn(II). Upon coupling with trastuzumab as a BFC ligand, it becomes an excellent imaging probe for HER2-positive tumors. [52Mn]Mn-BPPA-trastuzumab enables an extended imaging time window and earlier detection of HER2-positive tumors with superior tumor-to-background contrast.

MeSH terms

  • Animals
  • Cell Line, Tumor
  • Chelating Agents / chemical synthesis
  • Chelating Agents / chemistry
  • Female
  • Manganese* / chemistry
  • Manganese* / metabolism
  • Mice
  • Mice, Inbred BALB C
  • Mice, SCID*
  • Picolinic Acids / chemistry
  • Positron-Emission Tomography* / methods
  • Radiopharmaceuticals / chemical synthesis
  • Radiopharmaceuticals / chemistry
  • Radiopharmaceuticals / pharmacokinetics
  • Receptor, ErbB-2* / metabolism
  • Tissue Distribution
  • Trastuzumab* / chemistry

Substances

  • Chelating Agents
  • ERBB2 protein, human
  • Manganese
  • Picolinic Acids
  • Radiopharmaceuticals
  • Receptor, ErbB-2
  • Trastuzumab