Over the past few years, great progress has been made in the development of high-affinity adenosine A1 and/or A2A receptor antagonists – promising agents for the potential treatment of Parkinson’s disease. Unfortunately, many of these compounds raise structure-related concerns. The present study investigated the effect of ring closures on the rA1/A2A affinity of compounds containing a highly reactive α,β-unsaturated carbonyl system, hence providing insight into the potential of heterocycles to address these concerns. A total of twelve heterocyclic compounds were synthesised and evaluated in silico and in vitro. The test compounds performed well upon qualitative assessment of drug-likeness and were generally found to be free from potentially problematic fragments. Most also showed low/weak cytotoxicity. Results from radioligand binding experiments confirm that heterocycles (particularly 2-substituted 3-cyanopyridines) can replace the promiscuous α,β-unsaturated ketone functional group without compromising A1/A2A affinity. Structure-activity relationships highlighted the importance of hydrogen bonds in binding to the receptors of interest. Compounds 3c (rA1Ki = 16 nM; rA2AKi = 65 nM) and 8a (rA1Ki = 102 nM; rA2AKi = 37 nM), which both act as A1 antagonists, showed significant dual A1/A2A affinity and may, therefore, inspire further investigation into heterocycles as potentially safe and potent adenosine receptor antagonists.