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Background: Non-steroidal anti-inflammatory drugs (NSAIDs) that modulate gamma-secretase cleavage of amyloid precursor protein (APP) affect the distance between APP and presenilin, the catalytic subunit of gammasecretase. They seem to interfere with substrate recognition/cleavage and shift the precision of gamma-secretase cleavage from the beta-amyloid 42 to the beta-amyloid 38 site to generate more Abeta 38 and less Abeta 42.New data indicate binding of selected gamma-secretase modulators to the substrate to induce a stabilisation of a non-pathological conformation. Methods: The optimisation of NSAID derived lead structure and introduction of photocrosslinkable fragment furnished suitable tools to address the binding of gamma-secretase modulators. Fluorescent derivatives and tethered dimers are utilized to investigate presence and distance of potential multiple binding sites. Results: The binding site of flurbiprofen derived gamma-secretase modulators was mapped to the vicinity of the GXXXG motive of amyloid precursor protein. Conclusions: The established binding site of flurbiprofen derived gamma-secretase modulators resides close to the membrane surface and thus mandates a high lipophilicity in combination with a strongly acidic functional group. This combination is unusual for therapeutic drug, but common to amphilic tensides, thus creates an obstacle for drug development.