The detection of intermediate-mass black hole (IMBHs) i.e., those with mass ∼100–105 M⊙, is an emerging goal of gravitational-wave (GW) astronomy with wide implications for cosmology and tests of strong-field gravity. Current PyCBC-based searches for compact binary mergers, which match filtered the detector data against a set of template waveforms, have so far detected or confirmed several GW events. However, the sensitivity of these searches to signals arising from mergers of IMBH binaries is not optimal. Here, we present a new optimized PyCBC-based search for such signals. Our search benefits from using a targeted template bank, stricter signal-noise discriminators, and a lower matched-filter frequency cut-off. In particular, for a population of simulated signals with isotropically distributed spins, we improve the sensitive volume-time product over previous PyCBC-based searches at an inverse false alarm rate of 100 years, by a factor of 1.5 to 3 depending on the total binary mass. We deploy this new search on Advanced LIGO-Virgo data from the first half of the third observing run. The search does not identify any new significant IMBH binaries but does confirm the detection of the short-duration GW signal, GW190521, with a false alarm rate of 1 in 727 years.