A 99mTc(CO)3‐labeled benzylguanidine with persistent heart uptake

We describe the synthesis and biological evaluation of the cationic ^99mTc–tricarbonyl complex fac‐[^99mTc(CO)₃(κ³‐L1)]⁺ (Tc1) anchored by a pyrazole‐diamine‐methylbenzylguanidine‐based ligand (L1), as potentially useful for myocardial imaging. The rhenium complex fac‐[Re(CO)₃(κ³‐L1)]⁺ (Re1) was prepared and characterized as a ‘cold’ surrogate of the radioactive complex. Cell uptake studies in a neuroblastoma cell line suggest that Tc1 uptake mechanism is related to the norepinephrine transporter (NET). Tissue distribution studies in CD1 mice showed that Tc1 presents high initial heart uptake and a slow washout from the heart (7.8 ± 1.3% injected dose per gram (ID/g), 30‐min post‐injection (p.i.); 6.3 ± 1.3% ID/g, 60‐min p.i.), with heart to blood ratios of 11.8 and 9.0 at 30‐ and 60‐min p.i., respectively. The uptake mechanism of Tc1 appears to be similar to that of metaiodobenzylguanidine (MIBG), as it can be reduced by coinjection with nonradioactive MIBG. The biodistribution profile of Tc2, where the benzylguanidine pharmacophore is absent, corroborates the fact that Tc1 does not accumulate in the heart by a simple diffusion mechanism but rather by a NET‐mediated mechanism. The results confirm those obtained in the cell assays. Despite the persistent heart uptake found for Tc1, the high hepatic and renal uptake remains to be improved.