in Wiley InterScience (www.interscience.wiley.com).The addition reaction of lithium reagents to the 4 position of 2-chloropyrimidine or 2-chloroquinazoline followed by oxidation of the resultant dihydro intermediate product is a powerful tool for the synthesis of 4-substituted 2-chloropyrimidines or 2-chloroquinazolines. 4-Vinyl derivatives undergo a conjugate nucleophilic addition across the vinyl group. A nucleophilic displacement of chloride in 4-substituted 2-chloropyrimidines or 2-chloroquinazolines by treatment with 4-methylpiperazine provides compounds that are antagonists of the serotonin 5-HT 2A receptor.

F-1 exhibited a high specificity for the kidney, rapid renal excretion comparable to that of I-OIH and high in vivo radiochemical stability. Not only isF-1 a promising PET renal tracer, but it provides a route to the development of a pair of analogous F/Tc renal imaging agents with almost identical structures and comparable pharmacokinetic properties. These promising in vivo results warrant subsequent evaluation in humans.

We previously identified two new agents based on the [99mTcVO]3+ core with renal clearances in human volunteers 30% higher than that of the widely used clinical tracer 99mTc-MAG3 (MAG35− = penta-anion of mercaptoacetyltriglycine). However, renal agents with even higher clearances are needed. More recently, we changed our focus from the [99mTcVO]3+ core to the discovery of superior tracers based on the fac-[99mTcI(CO)3]+ core. Compared to 99mTc-MAG3, fac-[99mTcI(CO)3(NTA)]2− (NTA3− = tri-anion 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-[ReI(CO)3(NTA)]2− with a –CH2CO2− dangling monoanionic chain and on two fac-[ReI(CO)3(L)]− analogs with either a –CH2CONH2 or –CH2CH2OH dangling neutral chain. In these three fac-[ReI(CO)3(L)]n− complexes, the fac-[ReI(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-[99mTcI(CO)3(L)]− analogs with these neutral dangling chains were found to have pharmacokinetic properties very closely similar to those of fac-[99mTcI(CO)3(NTA)]2−. Therefore, we reach the unexpected conclusion that in fac-[99mTcI(CO)3(L)]n− agents, renal clearance is affected much more than anticipated by features of the core plus the chelate rings (the [99mTcI(CO)3(N(CH2CO2)2)]− moiety) than by the presence of a negatively charged dangling carboxylate chain.

The reaction of an aminopolycarboxylate ligand, aspartic-N-monoacetic acid (ASMA), with [Re(CO)3(H2O)3]+ was examined. The tridentate coordination of ASMA to this ReI tricarbonyl precursor yielded fac-Re(CO)3(ASMA) as a mixture of diastereomers. The chemistry is analogous to that of the TcI tricarbonyl complex, which yields fac-99mTc(CO)3(ASMA) under similar conditions. The formation, structure, and isomerization of fac-Re(CO)3(ASMA) products were characterized by HPLC, 1H NMR spectroscopy, and X-ray crystallography. The two major fac-Re(CO)3(ASMA) diastereomeric products each have a linear ONO coordination mode with two adjacent five-membered chelate rings, but they differ in the endo or exo orientation of the uncoordinated acetate group, in agreement with expectations based on previous studies. Conditions have been identified for the expedient isomerization of fac-Re(CO)3(ASMA) to a mixture consisting primarily of one major product. Because different isomeric species typically have different pharmacokinetic characteristics, these conditions may provide for the practical isolation of a single 99mTc(CO)3(ASMA) species, thus allowing the isolation of the isomer that has optimal imaging and pharmacokinetic characteristics. This information will aid in the design of future 99mTc radiopharmaceuticals.

Introduction 99mTc(CO)3-nitrilotriacetic acid, 99mTc(CO)3(NTA), is a new renal tubular agent with pharmacokinetic properties comparable to those of 131I-OIH but the clearance of 99mTc(CO)3(NTA) and 131I-OIH are still less than the clearance of PAH, the gold standard for the measurement of effective renal plasma flow. At physiological pH, dianionic 99mTc(CO)3(NTA) has a mononegative inner metal-coordination sphere and a mononegative uncoordinated carboxyl group. To evaluated alternate synthetic approaches, we assessed the importance of an uncoordinated carboxyl group, long considered essential for tubular transport, by evaluating the pharmacokinetics of three analogs with the 99mTc(CO)3(NTA) metal-coordination sphere but with uncharged pendant groups. Methods 99mTc(CO)3 complexes with N-(2-acetamido)iminodiacetic acid (ADA), N-(2-hydroxyethyl)iminodiacetic acid (HDA) and N-(fluoroethyl)iminodiacetic acid (FEDA) were prepared using a tricarbonyl kit and isolated by HPLC. The pharmacokinetics were evaluated in Sprague-Dawley rats, with 131I-OIH as an internal control; urine was analyzed for metabolites. Plasma protein binding and erythrocyte uptake were determined from the 10 min blood samples. Re(CO)3(FEDA), the analog of 99mTc(CO)3(FEDA), was prepared and characterized. Results 99mTc(CO)3(ADA), 99mTc(CO)3(HDA) and 99mTc(CO)3(FEDA) were efficiently prepared as a single species with high radiochemical purities (>99%). These new monoanionic 99mTc(CO)3 tracers with uncharged dangling groups all showed rapid blood clearance and high specificity for renal excretion. Activity in the urine, as a percent of 131I-OIH at 10 and 60 min, was 96% and 99% for ADA, 96% and 100% for HDA, and 100% and 99% for FEDA, respectively. Each new tracer was excreted unchanged in the urine. The Re(CO)3(FEDA) structure adds compelling evidence that such 99mTc(CO)3(NTA) analogs have metal-coordination spheres identical to that of 99mTc(CO)3(NTA). Conclusions New tracers lacking the negatively charged pendant carboxyl group previously thought to be essential for rapid renal extraction, 99mTc(CO)3(ADA), 99mTc(CO)3(HDA) and 99mTc(CO)3(FEDA), exhibit pharmacokinetics in rats comparable to those of 99mTc(CO)3(NTA) and 131I-OIH. Furthermore, these encouraging results in rats warrant evaluation of this new tracer type in humans.