A set of bivalent mannose 6-phosphonate 'molecular rulers' has been synthesized to examine ligand binding to the M6P/IGF2R. The set is estimated to span a P-P distance range of 16-26A (MMFF energy minimization on the hydrated phosphonates). Key synthetic transformations include sugar triflate displacement for phosphonate installation and Grubbs I cross-metathesis to achieve bivalency. Relative binding affinities were tested by radioligand displacement assays versus PMP-BSA (pentamannosyl phosphate-bovine serum albumin). These compounds exhibit slightly higher binding affinities for the receptor (IC(50)'s=3.7-5 microM) than the parent, monomeric mannose 6-phosphonate ligand and M6P itself (IC(50)=11.5+/-2.5 microM). These results suggest that the use of an alpha-configured anomeric alkane tether is acceptable, as no significant thermodynamic penalty is apparently paid with this design. On the other hand, the modest gains in binding affinity observed suggest that this ligand set has not yet found true bivalent interaction with the M6P/IGF2R (i.e., simultaneous binding to two distinct M6P-binding pockets).