Analogues Useful for Assessing the Excellent Renal Clearance of the fac ‐ [ 99 mTcI ( CO ) 3 ( NTA ) ] 2 − Diagnostic Renal Agent

We previously identified two new agents based on the [TcO] core with renal clearances in human volunteers 30% higher than that of the widely used clinical tracer Tc-MAG3 (MAG3 5− = penta-anion of mercaptoacetyltriglycine). However, renal agents with even higher clearances are needed. More recently, we changed our focus from the [TcO] core to the discovery of superior tracers based on the fac-[Tc(CO)3] + core. Compared to Tc-MAG3, fac-[ Tc(CO)3(NTA)] 2− (NTA3− = trianion of nitrilotriacetic acid) holds great promise by virtue of its efficient renal clearance via tubular secretion and the absence of hepatobiliary elimination, even in patients with severely reduced renal function. We report here NMR, molecular (X-ray) structure, and solution data on fac-[Re(CO)3(NTA)] 2− with a −CH2CO2 dangling monoanionic chain and on two fac-[Re(CO)3(L)] − analogues with either a −CH2CONH2 or a −CH2CH2OH dangling neutral chain. In these three fac-[Re(CO)3(L)] n− complexes, the fac-[Re(CO)3(N(CH2CO2)2)] − moiety is structurally similar and has similar electronic properties (as assessed by NMR data). In reported and ongoing studies, the two fac-[Tc(CO)3(L)] − analogues with these neutral dangling chains were found to have pharmacokinetic properties very similar to those of fac[Tc(CO)3(NTA)] 2−. Therefore, we reach the unexpected conclusion that in fac-[Tc(CO)3(L)] n− agents, renal clearance is affected much more than anticipated by features of the core plus the chelate rings (the [Tc(CO)3(N(CH2CO2)2)] − moiety) than by the presence of a negatively charged dangling carboxylate chain. ■ INTRODUCTION Tc radiopharmaceuticals are widely employed in nuclear medicine for imaging and for assessing physiological function and disease. The close relationship between Tc and Re chemistry has led to the use of the Re/Tc strategy of synthesizing and characterizing Re complexes and performing animal biodistribution studies with the Tc analogues. Renal Tc radiopharmaceuticals are used to image the kidney, evaluate suspected renal disease, and monitor renal function. Image quality is dependent on rapid removal of the radiotracer from the circulating plasma by the kidney; the rate of removal provides an important measurement of renal function. The rate-limiting factor for the removal of any substance by the kidney is the renal plasma flow, an important physiological parameter. This parameter could be measured indirectly with a nonmetabolized substance that is completely extracted with each circulation through the kidneys. The small aromatic compound, p-aminohippuric acid (PAH, Figure 1), approximates this ideal substance, and its clearance, termed the effective renal plasma flow (ERPF), has served as a benchmark for the indirect measurement of renal plasma flow. A radiopharmaceutical related to PAH, I-orthoiodohippuran (I-OIH, introduced in 1960, Figure 1), was subsequently demonstrated to have a clearance highly correlated with PAH and an I-OIH/PAH clearance ratio of 87%. The development of I-OIH was a major step forward. However, the relatively long half-life (8 days) and beta emission of I raised the possibility of delivering a large radiation dose to patients with reduced renal function; moreover, the 364 keV gamma photon emitted by I was too high in energy for an optimal imaging tracer. The limitations of I stimulated the development of Tc-based tracers. Tc has a short half-life (6 h) and lacks beta emission, features that minimize the radiation dose to patients; in addition, Tc emits a 140 keV photon optimal for imaging. However, a coordination complex could not be a close structural analogue of PAH. By the late 1980s, the best of several Tc tracers developed for imaging the kidneys and estimating ERPF was Tcmercaptoacetyltriglycine (Tc-MAG3, Figure 1), although the clearance of Tc-MAG3 was only 50−65% that of I-OIH, making the tracer suboptimal for the estimation of ERPF. Nevertheless, Tc-MAG3 is now the most commonly used radiotracer for this purpose, even though the Tc-MAG3 Received: March 13, 2015 Article