Research ArticleBasic Science Investigations

Synthesis and Preliminary Evaluation of Phenyl 4-123I-Iodophenylcarbamate for Visualization of Cholinesterases Associated with Alzheimer Disease Pathology

Ian R. Macdonald, G. Andrew Reid, Ian R. Pottie, Earl Martin and Sultan Darvesh
Journal of Nuclear Medicine February 2016, 57 (2) 297-302; DOI: https://doi.org/10.2967/jnumed.115.162032

Article Figures & Data

Figures

  • FIGURE 1.
    FIGURE 1.

    Schematic representation of interaction between cholinesterase catalytic serine and 123I-PIP showing slow dissociation of covalent intermediate containing 123I, a step occurring rapidly with ester substrates.

  • FIGURE 2.
    FIGURE 2.

    Structures of cholinesterase imaging agent 123I-PIP and β-amyloid imaging agent 123I-IMPY.

  • FIGURE 3.
    FIGURE 3.

    Synthesis of PIP (1), corresponding tributyltin precursor (2), and 123I-radiolabeled product (3, 123I-PIP). Et3N = triethylamine; NCS = N-chlorosuccinimide; Pd(PPh3)4 = tetrakis(triphenylphosphine)palladium(0); Sn2Bu6 = hexabutylditin; TIPSOTf = triisopropylsilyl trifluoromethanesulfonate.

  • FIGURE 4.
    FIGURE 4.

    Photomicrographs of representative human orbitofrontal cortex sections from normal/Aβ−, normal/Aβ+, and AD human orbitofrontal cortex showing in vitro autoradiography with 123I-PIP (3) and 123I-IMPY. In all AD brain tissue, sections labeled with 123I-IMPY and 123I-PIP (n = 74) visualized Aβ plaques. Aβ plaques in normal/Aβ+ sections were visualized with 123I-IMPY but were not labeled with 123I-PIP (n = 11). Sections of cortex from normal/Aβ− did not show accumulation of either 123I-PIP (n = 30) or 123I-IMPY. 123I-PIP (3) demonstrates selectivity for detection of Aβ plaques in AD brain and not those in cognitively normal brain. Arrows indicate Aβ plaques. Scale bar = 1 mm.

  • FIGURE 5.
    FIGURE 5.

    Photomicrographs of representative human orbitofrontal cortex sections from normal/Aβ−; normal/Aβ+; and AD cases showing histofluorescent staining with thioflavin-S (Th-S), autoradiography with 123I-IMPY, histochemical staining for AChE and BChE, and autoradiography with 123I-PIP (3). Accumulation of 123I-IMPY in cortex corresponded to Th-S–positive Aβ deposits in brain tissues from both AD and normal/Aβ+ individuals. Brain tissues from normal/Aβ− individuals did not show cortical accumulation of 123I-IMPY. Autoradiography of Aβ deposition with 123I-IMPY is not able to distinguish AD from normal/Aβ+. Accumulation of 123I-PIP (3) in sections of orbitofrontal cortex (n = 74) corresponded to BChE, AChE, and Th-S–positive Aβ deposits in AD only. Normal/Aβ+ tissues were positive for Th-S; however, BChE and AChE activity was not associated with these structures and 123I-PIP (3) also did not accumulate in these sections (n = 11). Similarly, normal/Aβ− tissues were devoid of plaque-associated cholinesterase activity, and 123I-PIP (3) did not accumulate in these sections (n = 30). Autoradiography of cholinesterase-associated Aβ deposition with 123I-PIP (3) is able to distinguish AD from normal/Aβ+. Arrows indicate plaques visualized using described methods. Scale bar = 500 μm.

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