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

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.