Re(I) and 99mTc(I) tricarbonyl complexes with ether-containing pyrazolyl-based chelators: Chemistry, biodistribution and metabolism

• Ether-containing 99mTc(I) complexes undergo in vivo metabolization.
• The metabolization affords alcohol and carboxylic acid derivatives.
• Despite the metabolization, the coordination sphere is retained in vivo.
• The metabolization might allow the tuning of the complexes pharmacokinetics.
• The tuning of pharmacokinetics is a key issue in radiopharmaceutical applications.

Tris(pyrazolyl)methane chelators, L1–L3, containing one or two ether groups at different positions of the azole rings, were synthesized and fully characterized. These chelators enabled the synthesis of fac-[99mTc(CO)3{HC[4-(ROCH2)pz]3}]+ (R = Me (Tc1), Et (Tc2)) and fac-[99mTc(CO)3{HC[3,5-(EtOCH2)2pz]3}]+ (Tc3) which were identified by HPLC in comparison with the rhenium counterparts. The evaluation of Tc1–Tc3 in CD-1 mice has shown that the number and/or nature of the ether groups greatly influence the biodistribution profile, pharmacokinetics and metabolic stability of these complexes. Tc1 and Tc2, bearing a unique ether substituent at the 4-position of the pyrazolyl ring, undergo metabolic transformation in vivo while Tc3 is not metabolized. The metabolization of Tc1 and Tc2 enhanced their rate of excretion but, most probably, also justify their negligible heart uptake in contrast with the high heart uptake of congener non-metabolizable complexes (99mTc-DMEOP and 99mTc-TMEOP), which have recently emerged as potential myocardial imaging agents.The attempts made to identify the metabolites of Tc1 and Tc2 have shown that the metabolization of these compounds must involve the ether functions with probable formation of carboxylic acid derivatives. A comparative study with the congener fac-[99mTc(CO)3{[4-(MeOCH2)pz](CH2)2NH(CH2)2NH2}]+ (Tc6) led us to confirm the formation of such type of metabolites. In fact, Tc6 is also metabolized in mice with formation of fac-[99mTc(CO)3{[4-(HOCH2)pz](CH2)2NH(CH2)2NH2}]+ (Tc7) and fac-[99mTc(CO)3{[4-(HOOC)pz](CH2)2NH(CH2)2NH2}]+ (Tc8), which were chemically identified by HPLC in comparison with the Re congeners (Re7 and Re8).

We have proved that ether-containing 99mTc complexes are metabolized in vivo with formation of alcohol and carboxylic acid derivatives. Such metabolization does not affect the coordination sphere of the complexes and might allow the tuning of the corresponding pharmacokinetics, which is a key issue in radiopharmaceutical applications.Figure optionsDownload as PowerPoint slide