Initial evaluation of new 99mTc(CO)3 renal imaging agents having carboxyl-rich thioether ligands and chemical characterization of ReCO3 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)I-orthoiodohippurate ((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 degrees C (pH 7) for 30 min. The products were purified by reversed-phase high-performance liquid chromatography, 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)Tc(CO)(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 5-membered chelate rings). Renal excretion at 60 min (activity in the urine as a percentage 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.

Chart 1

Figure 1

Perspective drawing of [NMe₄][Re(CO)₃(CMSAH)] with 50% probability for the atomic displacement parameters. The [NMe₄]⁺ cation is omitted for clarity. Selected bond angles (°): O(4)-Re(1)-S(1), 79.94(6); O(6)-Re(1)-S(1), 80.29(7); O(4)-Re(1)-O(6), 83.76(8). Selected bond distances (Å): Re(1)-O(4), 2.164(2); Re(1)-O(6), 2.127(2); Re(1)-S(1), 2.4515(8).

Figure 2

Overlay of the computed minimized structure (dark) and the X-ray structure (light) of [Re(CO)₃(CMSAH)]⁻.

Figure 3

Computed minimized structures of the two isomers of [Re(CO)₃(CMSA)]²⁻ with the carboxyl group pointing away from (upper left) or toward (upper right) the OSO coordination face. Also shown are minimized structures of the two isomers of [Re(CO)₃(meso-TDSA)]³⁻ with the two carboxyl groups pointing away from (bottom left) or toward (bottom right) the OSO coordination face.

Figure 4

Radio-HPLC traces of rats urine samples (15 min p.i.). The rat was injected with [^99mTc(CO)₃(CMSA)]²⁻ (A) and [^99mTc(CO)₃(TDSA)]³⁻ (B). The corresponding reference HPLC traces showed that both complexes were excreted unchanged in urine.