Re and ^99mTc organometallic complexes containing pendant L-arginine derivatives as potential probes of inducible nitric oxide synthase

Aiming to design radioactive compounds based on the core “^99mTc(CO)₃” for probing inducible nitric oxide synthase (iNOS) levels in vivo, we have synthesized conjugates containing a pyrazolyl-diamine chelating unit and pendant L-arginine analogues (substrates and inhibitors of NOS). Reaction of the conjugates with fac-[M(CO)₃]⁺ (M = Re, ^99mTc) gave bioorganometallic complexes of the type fac-[M(CO)₃(k³-L)] in good yield. After in vitro testing using the oxyhemoglobin NO capture assay, we concluded that the affinity of the inhibitor-containing conjugates to iNOS seems to be less affected upon metallation with rhenium than the substrate-containing conjugates. The complexes bearing guanidino substituted analogues of L-arginine still present considerable inhibitory action (N^ω-monomethyl-L-arginine, K_i = 36 μM; N^ω-nitro-L-arginine, K_i = 84 μM), being the first examples of organometallic complexes able to inhibit the iNOS. These results seem to indicate that ^99mTc(CO)₃-labeled L-argininine analogues, namely NOS inhibitors, may hold potential for monitoring increased levels of iNOS in vivo.