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Robust Quantification of Phosphodiesterase-4D in Monkey Brain with PET and 11C-Labeled Radioligands That Avoid Radiometabolite Contamination.
Jiang, Meijuan; Tang, Shiyu; Jenkins, Madeline D; Lee, Adrian C; Kenou, Bruny; Knoer, Carson; Montero Santamaria, Jose; Wu, Shawn; Liow, Jeih-San; Zoghbi, Sami S; Zanotti-Fregonara, Paolo; Innis, Robert B; Telu, Sanjay; Pike, Victor W.
Afiliación
  • Jiang M; Molecular Imaging Branch, National Institute of Mental Health, National Institutes of Health, Bethesda, Maryland.
  • Tang S; Molecular Imaging Branch, National Institute of Mental Health, National Institutes of Health, Bethesda, Maryland.
  • Jenkins MD; Molecular Imaging Branch, National Institute of Mental Health, National Institutes of Health, Bethesda, Maryland.
  • Lee AC; Molecular Imaging Branch, National Institute of Mental Health, National Institutes of Health, Bethesda, Maryland.
  • Kenou B; Molecular Imaging Branch, National Institute of Mental Health, National Institutes of Health, Bethesda, Maryland.
  • Knoer C; Molecular Imaging Branch, National Institute of Mental Health, National Institutes of Health, Bethesda, Maryland.
  • Montero Santamaria J; Molecular Imaging Branch, National Institute of Mental Health, National Institutes of Health, Bethesda, Maryland.
  • Wu S; Molecular Imaging Branch, National Institute of Mental Health, National Institutes of Health, Bethesda, Maryland.
  • Liow JS; Molecular Imaging Branch, National Institute of Mental Health, National Institutes of Health, Bethesda, Maryland.
  • Zoghbi SS; Molecular Imaging Branch, National Institute of Mental Health, National Institutes of Health, Bethesda, Maryland.
  • Zanotti-Fregonara P; Molecular Imaging Branch, National Institute of Mental Health, National Institutes of Health, Bethesda, Maryland.
  • Innis RB; Molecular Imaging Branch, National Institute of Mental Health, National Institutes of Health, Bethesda, Maryland.
  • Telu S; Molecular Imaging Branch, National Institute of Mental Health, National Institutes of Health, Bethesda, Maryland pikev@mail.nih.gov sanjay.telu@nih.gov.
  • Pike VW; Molecular Imaging Branch, National Institute of Mental Health, National Institutes of Health, Bethesda, Maryland pikev@mail.nih.gov sanjay.telu@nih.gov.
J Nucl Med ; 65(5): 788-793, 2024 May 01.
Article en En | MEDLINE | ID: mdl-38423785
ABSTRACT
Phosphodiesterase-4D (PDE4D) has emerged as a significant target for treating neuropsychiatric disorders, but no PET radioligand currently exists for robustly quantifying human brain PDE4D to assist biomedical research and drug discovery. A prior candidate PDE4D PET radioligand, namely [11C]T1650, failed in humans because of poor time stability of brain PDE4D-specific signal (indexed by total volume of distribution), likely due to radiometabolites accumulating in brain. Its nitro group was considered to be a source of the brain radiometabolites.

Methods:

We selected 5 high-affinity and selective PDE4D inhibitors, absent of a nitro group, from our prior structure-activity relationship study for evaluation as PET radioligands.

Results:

All 5 radioligands were labeled with 11C (half-time, 20.4 min) in useful yields and with high molar activity. All displayed sizable PDE4D-specific signals in rhesus monkey brain. Notably, [11C]JMJ-81 and [11C]JMJ-129 exhibited excellent time stability of signal (total volume of distribution). Furthermore, as an example, [11C]JMJ-81 was found to be free of radiometabolites in ex vivo monkey brain, affirming that this radioligand can provide robust quantification of brain PDE4D with PET.

Conclusion:

Given their high similarity in structures and metabolic profiles, both [11C]JMJ-81 and [11C]JMJ-129 warrant further evaluation in human subjects. [11C]JMJ-129 shows a higher PDE4D specific-to-nonspecific binding ratio and will be the first to be evaluated.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Encéfalo / Radioisótopos de Carbono / Tomografía de Emisión de Positrones / Fosfodiesterasas de Nucleótidos Cíclicos Tipo 4 / Macaca mulatta Límite: Animals / Humans / Male Idioma: En Revista: J Nucl Med Año: 2024 Tipo del documento: Article Pais de publicación: Estados Unidos
Texto completo
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Encéfalo / Radioisótopos de Carbono / Tomografía de Emisión de Positrones / Fosfodiesterasas de Nucleótidos Cíclicos Tipo 4 / Macaca mulatta Límite: Animals / Humans / Male Idioma: En Revista: J Nucl Med Año: 2024 Tipo del documento: Article Pais de publicación: Estados Unidos