The family reached is peak under the Palaiologan emperors in the late 13th and first half of the 14th century: John Synadenos married Theodora Palaiologina, the niece of Emperor Michael VIII Palaiologos, and served as megas stratopedarches, and his sons John and Theodore likewise held senior military commands.
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At this time, the Synadenoi intermarried with two other prominent aristocratic families, the Asen and the Raoul.
Synadenos was a close friend to his cousin, the junior emperor Michael IX Palaiologos, but after Michael's death in 1320, Michael's father, the old emperor Andronikos II (r. 1282–1328), distrusting his loyalty, sent him to the border with Serbia, as governor of Prilep.