| Abstract
| - Radiolabeling of biologically active molecules with the [99mTc(CO)3]+ unit has been of primary interestin recent years. With this in mind, we herein report symmetric (L1) and asymmetric (L2−L5) pyrazolyl-containing chelators that have been evaluated in radiochemical reactions with the synthon[99mTc(H2O)3(CO)3]+ (1a). These reactions yielded the radioactive building blocks [99mTc(CO)3(k3-L)]+(L = L1−L5, 2a−6a), which were identified by RP-HPLC. The corresponding Re surrogates (2−6)allowed for macroscopic identification of the radiochemical conjugates. Complexes 2a−6a, with logPo/w values ranging from −2.35 to 0.87, were obtained in yields of ≥90% using ligand concentrationsin the 10-5-10-4 M range. Challenge studies with cysteine and histidine revealed high stability forall of these radioactive complexes, and biodistribution studies in mice indicated a fast rate of bloodclearance and high rate of total radioactivity excretion, occurring primarily through the renal-urinarypathway. Based on the framework of the asymmetric chelators, the novel bifunctional ligands 3,5-Me2-pz(CH2)2N((CH2)3COOH)(CH2)2NH2 (L6) and pz(CH2)2N((CH2)3COOH)(CH2)2NH2 (L7) have beensynthesized and their coordination chemistry toward (NEt4)2[ReBr3(CO)3] (1) has been explored. Theresulting complexes, fac-[Re(CO)3(k3-L)]Br (L6 (7), L7(8)), contain tridentate ancillary ligands thatare coordinated to the metal center through the pyrazolyl and amine nitrogen atoms, as observed forthe other related building blocks. L6 and L7 were coupled to a glycylglycine ethyl ester dipeptide, andthe resulting functionalized ligands were used to prepare the model complexes fac-[Re(CO)3(κ3-3,5-Me2-pz(CH2)2N(glygly)(CH2)2NH2)]+ (9/9a) and fac-[Re(CO)3(κ3-pz(CH2)2N(CH2)3(glygly)(CH2)2NH2)]+(10/10a) (M = Re, 99mTc). These small conjugates have been fully characterized and are reported herein.On the basis of the in vitro/in vivo behavior of the model complexes (2a−6a, 9a, 10a), we chose toevaluate the in vitro/in vivo biological behavior of a new tumor-seeking Bombesin pyrazolyl conjugate,[(L6)-G-G-G-Q-W-A-V-G-H-L-M-NH2], that has been labeled with the [99mTc(CO)3]+ metal fragment.Stability, in vitro cell binding assays, and pharmacokinetics studies in normal mice are reported herein.
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