Development and preclinical evaluation of radioligands for the PET studies of cerebral adenosine A1 and A2A receptors

Shivashankar Shivashankar

    Research output: ThesisThesis fully internal (DIV)

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    Abstract

    Because of the clinical importance of A1Rs and A2ARs, the development of high affinity and subtype-selective radioligands for mapping AR density is urgently needed. The main objective of this thesis is to develop A2AR tracers with a high degree of selectivity, sufficient affinity to image receptors but not so high as to compromise receptor quantification, good pharmacokinetic properties, and larger target-to-nontarget ratios than existing radiotracers such as [11C]SCH442416.

    A retrosynthetic approach was adopted for the synthesis of nonradioactive fluorinated SCH442416 analogues and O-desmethyl preladenant. [18F]Fluoropropyl SCH442416 ([18F]FPSCH) and [11C]Preladenant were developed as new PET ligands for mapping cerebral adenosine A2A receptors (A2ARs). Fluorinated ligands can provide logistic advantages over C-11 labeled tracers, and be distributed to remote centers without an expensive on-site cyclotron. The two tracers mentioned above were synthesized in high specific activity and purity. Tracer tissue distribution was studied by PET, ex-vivo analysis and in vitro autoradiography. The regional uptake of [18F]FPSCH and [11C]preladenant was consistent with known A2ARs distribution in the rat brain, with highest uptake in striatum. PET showed that [18F]FPSCH and [11C]preladenant have favorable cerebral kinetics. Both tracers exhibit suitable characteristics for PET imaging of A2ARs.
    Translated title of the contributionOntwikkeling en preklinische evaluatie van radioliganden voor PET-studies van adenosine A1 en A2a receptoren in het brein
    Original languageEnglish
    QualificationDoctor of Philosophy
    Awarding Institution
    • University of Groningen
    Supervisors/Advisors
    • Elsinga, Philip, Supervisor
    • Dierckx, Rudi, Supervisor
    • van Waarde, Aren, Co-supervisor
    Award date15-Sep-2014
    Place of Publication[S.l.]
    Publisher
    Print ISBNs978-90-367-7226-6
    Electronic ISBNs978-90-367-7225-9
    Publication statusPublished - 2014

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