First evaluation of a 99mTc-tricarbonyl complex, 99mTc(CO)3(LAN), as a new renal radiopharmaceutical in humans

Abstract

(99m)Tc-Mercaptoacetyltriglycine ((99m)Tc-MAG3), (99m)Tc-dd- and ll-ethylene-dicysteine ((99m)Tc-EC), and (99m)Tc-mercaptoacetamide-ethylene-cysteine ((99m)Tc-MAEC) contain N(3)S or N(2)S(2) ligands designed to accommodate the 4 ligating sites of the ((99m)TcO)(3+) core; they are all excellent renal imaging agents but have renal clearances lower than that of (131)I-orthoiodohippurate ((131)I-OIH). To explore the potential of the newly accessible but less polar [(99m)Tc(CO)(3)](+) core with 3 ligating sites, we decided to build on the success of (99m)Tc-EC, with its N(2)S(2) ligand and 2 dangling carboxylate groups; we chose an N(2)S ligand that also has 2 dangling carboxylate groups, lanthionine, to form (99m)Tc(CO)(3)(LAN), a new renal radiopharmaceutical.

Methods: Biodistribution studies were performed on Sprague-Dawley rats with (99m)Tc(CO)(3)(LAN) isomers, meso-LAN and dd,ll-LAN (an enantiomeric mixture), coinjected with (131)I-OIH. Human studies also were performed by coinjecting each (99m)Tc-labeled product ( approximately 74 MBq [ approximately 2 mCi]) and (131)I-OIH ( approximately 7.4 MBq [ approximately 0.2 mCi]) into 3 healthy volunteers and then performing dual-isotope imaging by use of a camera system fitted with a high-energy collimator. Blood samples were obtained from 3 to 90 min after injection, and urine samples were obtained at 30, 90, and 180 min.

Results: Biodistribution studies in rats revealed rapid blood clearance as well as rapid renal extraction for both preparations, with the dose in urine at 60 min averaging 88% that of (131)I-OIH. In humans, both agents provided excellent renal images, with the plasma clearance averaging 228 mL/min for (99m)Tc(CO)(3)(meso-LAN) and 176 mL/min for (99m)Tc(CO)(3)(dd,ll-LAN). At 3 h, both (99m)Tc(CO)(3)(meso-LAN) and (99m)Tc(CO)(3)(dd,ll-LAN) showed good renal excretion, averaging 85% and 77% that of (131)I-OIH, respectively. Plasma protein binding was minimal (10% and 2%, respectively), and erythrocyte uptake was similar (24% and 21%, respectively) for (99m)Tc(CO)(3)(meso-LAN) and (99m)Tc(CO)(3)(dd,ll-LAN).

Conclusion: Although the plasma clearance and the rate of renal excretion of the (99m)Tc(CO)(3)(LAN) complexes were still lower than those of (131)I-OIH, the results of this first application of a (99m)Tc-tricarbonyl complex as a renal radiopharmaceutical in humans demonstrate that (99m)Tc(CO)(3)(LAN) complexes are excellent renal imaging agents and support continued renal radiopharmaceutical development based on the (99m)Tc-tricarbonyl core.

FIGURE 1

Comparison of ^99mTc-EC and ^99mTc(CO)₃(LAN), two agents with two-carboxylate structural features.

FIGURE 2

(A) displays the ^99mTc(CO)₃(LAN) images and curves obtained from a 27-year-old female volunteer who received an intravenous injection containing 62.9 MBq (1.7 mCi) of ^99mTc(CO)₃(meso-LAN) and 7.03 MBq (0.19 mCi) of ¹³¹I-OIH followed by 24-minutes of data acquisition. Demographics and renogram data (relative uptake (% uptake), time to maximum counts (Tmax (min)), time to half maximum counts (T1/2 (min)), and the twenty minute to maximum count ratio (20/max) for the whole kidney region of interest) are displayed in the upper left panel. The middle upper panel shows flow images at 2-sec/frame. An image containing the injection site in her arm (right upper panel) showed no infiltration. The center panel shows good uptake by the kidneys bilaterally with prompt excretion into the bladder. Whole kidney renogram curves are shown in the left lower panel and cortical renogram curves in the right lower panel; and (B) displays the ¹³¹I-OIH images and renogram curves obtained from the volunteer described in (A) using identical regions of interest over the whole kidney and cortex. The ¹³¹I-OIH renogram curves are much noisier than the ^99mTc(CO)₃(LAN) renogram curves because of the lower dose of ¹³¹I-OIH and the fact that the camera is not optimized to image the high energy photon of ¹³¹I.

FIGURE 2

(A) displays the ^99mTc(CO)₃(LAN) images and curves obtained from a 27-year-old female volunteer who received an intravenous injection containing 62.9 MBq (1.7 mCi) of ^99mTc(CO)₃(meso-LAN) and 7.03 MBq (0.19 mCi) of ¹³¹I-OIH followed by 24-minutes of data acquisition. Demographics and renogram data (relative uptake (% uptake), time to maximum counts (Tmax (min)), time to half maximum counts (T1/2 (min)), and the twenty minute to maximum count ratio (20/max) for the whole kidney region of interest) are displayed in the upper left panel. The middle upper panel shows flow images at 2-sec/frame. An image containing the injection site in her arm (right upper panel) showed no infiltration. The center panel shows good uptake by the kidneys bilaterally with prompt excretion into the bladder. Whole kidney renogram curves are shown in the left lower panel and cortical renogram curves in the right lower panel; and (B) displays the ¹³¹I-OIH images and renogram curves obtained from the volunteer described in (A) using identical regions of interest over the whole kidney and cortex. The ¹³¹I-OIH renogram curves are much noisier than the ^99mTc(CO)₃(LAN) renogram curves because of the lower dose of ¹³¹I-OIH and the fact that the camera is not optimized to image the high energy photon of ¹³¹I.

FIGURE 3

Urine samples from human volunteers injected with ^99mTc(CO)₃(meso-LAN) (panel A) and ^99mTc(CO)₃(dd,ll-LAN) (panel B) were subjected to γ-radioactive reversed-phase HPLC analysis. Corresponding reference HPLC traces show that both complexes were excreted unchanged in the urine.

FIGURE 4

Schematic drawing of the spatial relationships of the carboxylate groups (CO₂) to each other and to the plane defined by donor atoms in ^99mTc-EC and ^99mTc(CO)₃(LAN) complexes.