New ^99mTc(CO)₃(NNO) complexes in the development of 5HT_1A receptor imaging agents

Abstract

In this work we report the synthesis, characterization and biological evaluation of two new neutral tricarbonyl fac-M(CO)₃(NNO) (M=Re, ^99mTc) derivatives of WAY-100635 as potential ^99mTc agents for the in vivo imaging of 5HT_1A receptors. The new pharmacophore NNO ligands are based on the picolylamine N,N-diacetic acid (PADA) ligand and their synthesis was achieved through the PADA anhydride, showing thus the applicability of this synthetic approach, developed in our laboratory, for the incorporation of bioactive amines in the PADA molecule and the development of target specific radiopharmaceuticals. The rhenium complexes were synthesized using [NEt₄]₂[Re(CO)₃Br₃] as a precursor and fully characterized by elemental analysis and spectroscopic methods. The analogous technetium-99m complexes were also prepared quantitatively using the [^99mTc(CO)₃(H₂O)₃]⁺ precursor and their structure corroborated by means of the rhenium complexes. The lipophilicity of the Tc complexes is in the range normally accepted for substances to be able to cross the BBB. Competition binding tests showed moderate affinity for the 5HT_1A receptors, with IC₅₀ values at the nanomolar range (30 and 116 nM). Biodistribution in healthy animals was characterized by high initial blood and liver uptake and fast blood and tissue depuration with excretion taking place mainly through the hepatobiliary system. None of the new complexes showed any significant brain uptake, suggesting that the ability of a compound to cross the BBB is determined by more factors than charge, lipophilicity and size.