Picolinic acid based acyclic bifunctional chelating agent and its methionine conjugate as potential SPECT imaging agents: syntheses and preclinical evaluation

Abstract

Bifunctional chelate, 6,6′-(2-aminoethylazanediyl)bis(methylene)dipicolinic acid (H₂pentapa-en-NH₂), has been synthesized and labeled with ^99mTc with a specific activity of 135–140 MBq μmol⁻¹ in >95% yield. The in vitro stability of the labeled chelate in both PBS and human serum shows only <5% dissociation at 24 h. The in vivo distribution pattern of the labeled chelator in normal as well as EAT tumor bearing BALB/c mice suggested renal as the major route of excretion with <2% ID g⁻¹ uptake in other organs. The target specificity of the chelate towards tumor was introduced by conjugating two molecules of methionine. The conjugated probe H₂pentapa-en-met₂ was synthesized in >85% yield and labeled with ^99mTc in 96.2% radiochemical yield with a specific activity of 110–125 MBq μmol⁻¹. The conjugate probe exhibited high serum stability (>94% at 24 h). The in vivo blood kinetic studies of radiocomplexes of H₂pentapa-en-NH₂ and its methionine conjugated derivative exhibited fast clearance with t_1/2(F) = 32 ± 0.14 min, t_1/2(S) = 4 h 20 min ± 0.21 min and t_1/2(F) = 27 ± 0.3 min, t_1/2(S) = 4 h 01 min ± 0.11 min, respectively. In vivo scintigraphy and ex vivo biodistribution studies in EAT tumor bearing mice demonstrated a high retention of H₂pentapa-en-met₂ at the site of the tumor with tumor to muscle ratio of 6.52 at 1 h, indicating the high specificity of ^99mTc-pentapa-en-met₂ toward tumors.