Initial evaluation of new 99mTc(CO)3 renal imaging agents having carboxyl-rich thioether ligands and chemical characterization of Re(CO)3 analogues

Abstract

Introduction:The first human studies of a characterized radiopharmaceutical containing a { 99m Tc (CO) 3 } + core, Na[ 99m Tc(CO) 3 (LAN)], demonstrated that Na[ 99m Tc(CO) 3 (LAN)] was an excellent renal imaging agent however, its clearance was less than that of 131 Iorthoiodohippurate ( 131 I-OIH) and it did not provide a direct measure of effective renal plasma flow. In order to develop a 99m Tc renal agent with pharmacokinetic properties equivalent to those of 131 I-OIH, we investigated the 99m Tc(CO) 3 /Re(CO) 3 complexes formed from carboxymethylmercaptosuccinic acid (CMSAH 3 ) and thiodisuccinic acid (TDSAH 4 ). Once the ligand is bound to 99m Tc(CO) 3 through a thioether and two carboxyl groups, the complexes have at least one unbound carboxyl group, essential for the interaction with the renal tubular transporter.Methods: X-ray crystal structural analysis of NMe 4 [Re(CO) 3 (CMSAH)] was performed to interpret the nature of 99m Tc tracers. CMSAH 3 and TDSAH 4 were radiolabeled by incubating each ligand and the precursor [ 99m Tc(CO) 3 (H 2 O) 3 ] + at 70 °C (pH 7) for 30 min. The products were purified by RP-HPLC and biodistribution studies were performed in Sprague-Dawley rats, with 131 I-OIH as an internal control at 10 and 60 min.Results: Radiolabeling CMSAH 3 and TDSAH 4 with the [ 99m TcCO) 3 (H 2 O) 3 ] + precursor gave products quantitatively. Analysis of the Re(CO) 3 complexes with the CMSAH 3 and TDSAH 4 ligands demonstrates that ligands are bound in 99m Tc /Re(CO) 3 complexes through a thioether and two deprotonated carboxyl groups (forming tridentate dianionic moieties, generally with two fivemembered chelate rings). Renal excretion at 60 min (activity in the urine as a percent of 131 I-OIH) was 68 ± 1% for Na 3 [ 99m Tc(CO) 3 (TDSA)], but was 98 ± 1% for Na 2 [ 99m Tc(CO) 3 (CMSA)]. Conclusion:In rats, Na 2 [ 99m Tc(CO) 3 (CMSA)] is extracted by the kidneys and eliminated in the urine almost as rapidly as 131 I-OIH; consequently Na 2 [ 99m Tc(CO) 3 (CMSA)] may provide a direct measure of effective renal plasma flow and further evaluation in humans is warranted.

New Monodentate Amidine Superbasic Ligands with a Single Configuration infac-[Re(CO)3(5,5′- or 6,6′-Me2bipyridine)(amidine)]BF4Complexes

“…Thus, the investigation of fac -[Re I (CO) 3 L] n complexes both aids in interpreting the chemistry of the radiopharmaceuticals and offers the potential for the discovery of new chemistry, some of which could be applied to radiopharmaceutical development. 18–19 …”

Preclinical Evaluation of 99mTc(CO)3-Aspartic-N-Monoacetic Acid, a Renal Radiotracer with Pharmacokinetic Properties Comparable to 131I-o-Iodohippurate

“…Such amino acid analogues can provide three potential coordinating groups positioned to coordinate tridentately and facially to the {M(CO) 3 } + center to form stable 99m Tc/Re complexes. Our analysis of the charge and charge distribution of the tricarbonyl complexes suggests that a negative inner coordination sphere and an overall dianionic charge at physiological pH favor rapid renal tubular secretion (24, 28, 37). The best example of a 99m Tc-tricarbonyl renal tracer meeting these charge requirements and having an aminopolycarboxylate ligand is 99m Tc(CO) 3 (NTA).…”

“…The HPLC chromatograms for the 99m Tc tracers were obtained by use of a Beckman System Gold Nouveau apparatus equipped with a model 170 radiometric detector and a model 166 ultraviolet light-visible light detector, and a Beckman C18 RP Ultrasphere octyldecyl silane column (5-μm, 4.6 × 250 mm). The flow rate of the mobile phase was 1 mL/min, the mobile phase consisted of aqueous 0.05 M triethylammonium phosphate buffer pH 2.5 (solvent A) and methanol (solvent B), and the gradient method used was the same as reported previously (28). Tissue/organ radioactivity was measured using an automated 2480 Wizard 2 gamma counter (Perkin Elmer) with a 3-inch NaI(Tl) detector.…”

Monoanionic 99m Tc-tricarbonyl-aminopolycarboxylate complexes with uncharged pendant groups: Radiosynthesis and evaluation as potential renal tubular tracers

“…More recently, a completely new class of renal tracers based on the 99m Tc I (CO) 3 core and highly hydrophilic ligands has been developed and evaluated in rats; ligands examined in such 99m Tc-tricarbonyl tracers include nitrilotriacetic acid [in 99m Tc(CO) 3 (NTA)] [22], aspartic- N -monoacetic acid [in 99m Tc(CO) 3 (ASMA)] [23], carboxymethylmercaptosuccinic acid [in 99m Tc(CO) 3 (CMSA)] [24], thiodisuccinic acid [in 99m Tc(CO) 3 (TDSA)] [24], lanthionine [in 99m Tc(CO) 3 (LAN)] [25], ethylenediamine- N , N ’-diacetic acid [in 99m Tc(CO) 3 (ENDAC)] [26], and carboxymethylthioethyliminodiacetic acid [in 99m Tc(CO) 3 (CMT-IDA)] [27]. The 99m Tc(CO) 3 (NTA), 99m Tc(CO) 3 (ASMA) and 99m Tc(CO) 3 (CMSA) tracers were rapidly extracted by the kidney and eliminated in the urine in rats almost as fast as 131 I-OIH [22–24].…”

“…The 99m Tc(CO) 3 (NTA), 99m Tc(CO) 3 (ASMA) and 99m Tc(CO) 3 (CMSA) tracers were rapidly extracted by the kidney and eliminated in the urine in rats almost as fast as 131 I-OIH [22–24]. These three 99m Tc-tricarbonyl tracers have a negatively charged inner coordination sphere and a dianionic overall charge at physiological pH [24, 28, 29]; in addition, they also contain the free carboxylate group found in 99m Tc-MAG3, 99m Tc-EC and 99m Tc-MAEC and the other 99m Tc V O renal tracers. Furthermore, 99m Tc(CO) 3 (NTA) has been shown to have pharmacokinetic properties comparable to those of 131 I-OIH in normal volunteers [30] and also in patients with severely reduced renal function [31].…”