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@ARTICLE{Shojaei:269527,
      author       = {Shojaei, Monireh and Zhou, Qihui and Palumbo, Giovanna and
                      Schaefer, Rebecca and Kaskinoro, Janne and Vehmaan-Kreula,
                      Pirjo and Bartenstein, Peter and Brendel, Matthias and
                      Edbauer, Dieter and Lindner, Simon},
      title        = {{D}evelopment and {P}reclinical {E}valuation of a
                      {C}opper-64-{L}abeled {A}ntibody {T}argeting
                      {G}lycine-{A}lanine {D}ipeptides for {PET} {I}maging of
                      {C}9orf72-{A}ssociated {A}myotrophic {L}ateral
                      {S}clerosis/{F}rontotemporal {D}ementia},
      journal      = {ACS pharmacology $\&$ translational science},
      volume       = {7},
      number       = {5},
      issn         = {2575-9108},
      address      = {Washington, DC},
      publisher    = {ACS Publications},
      reportid     = {DZNE-2024-00568},
      pages        = {1404 - 1414},
      year         = {2024},
      abstract     = {Aggregating poly(glycine-alanine) (poly-GA) is derived from
                      the unconventional translation of the pathogenic intronic
                      hexanucleotide repeat expansion in the C9orf72 gene, which
                      is the most common genetic cause of frontotemporal dementia
                      (FTD) and amyotrophic lateral sclerosis (ALS). Poly-GA
                      accumulates predominantly in neuronal cytoplasmic inclusions
                      unique to C9orf72 ALS/FTD patients. Poly-GA is, therefore, a
                      promising target for PET/CT imaging of FTD/ALS to monitor
                      disease progression and therapeutic interventions. A novel
                      64Cu-labeled anti-GA antibody (mAb1A12) targeting the
                      poly-GA protein was developed and evaluated in a transgenic
                      mouse model. It was obtained with high radiochemical purity
                      (RCP), radiochemical yield (RCY), and specific activity, and
                      showed high stability in vitro and ex vivo and specifically
                      bound to poly-GA. The affinity of NODAGA-mAb1A12 for poly-GA
                      was not affected by this modification.
                      [64Cu]Cu-NODAGA-mAb1A12 was injected into transgenic mice
                      expressing GFP-(GA)175 in excitatory neurons driven by
                      Camk2a-Cre and in control littermates. PET/CT imaging was
                      performed at 2, 20, and 40 h post-injection (p.i.) and
                      revealed a higher accumulation in the cortex in transgenic
                      mice than in wild-type mice, as reflected by higher
                      standardized uptake value ratios (SUVR) using the cerebellum
                      as the reference region. The organs were isolated for
                      biodistribution and ex vivo autoradiography. Autoradiography
                      revealed a higher cortex-to-cerebellum ratio in the
                      transgenic mice than in the controls. Results from
                      autoradiography were validated by immunohistochemistry and
                      poly-GA immunoassays. Moreover, we confirmed antibody uptake
                      in the CNS in a pharmacokinetic study of the perfused
                      tissues. In summary, [64Cu]Cu-NODAGA-mAb1A12 demonstrated
                      favorable in vitro characteristics and an increased relative
                      binding in poly-GA transgenic mice compared to wild-type
                      mice in vivo. Our results with this first-in-class
                      radiotracer suggested that targeting poly-GA is a promising
                      approach for PET/CT imaging in FTD/ALS.},
      cin          = {AG Edbauer / AG Haass / AG Zhou},
      ddc          = {610},
      cid          = {I:(DE-2719)1110004 / I:(DE-2719)1110007 /
                      I:(DE-2719)5000080},
      pnm          = {352 - Disease Mechanisms (POF4-352)},
      pid          = {G:(DE-HGF)POF4-352},
      typ          = {PUB:(DE-HGF)16},
      pmc          = {pmc:PMC11091963},
      pubmed       = {pmid:38751620},
      doi          = {10.1021/acsptsci.4c00037},
      url          = {https://pub.dzne.de/record/269527},
}