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Aiming to evaluate their potential as radioactive probes for in vivo targeting of melanotic melanoma and its metastases, we have synthesized 99m Tc(I) tricarbonyl complexes (Tc1-Tc8) anchored by pyrazolyl-containing chelators with (N 3 ) or (N 2 O) donor atom sets and functionalized with 2-aminoethyldiethylamine and 4-amino-N-(2-diethylaminoethyl)benzamide groups as melanin-binding pharmacophores. The chemical identification of the several 99m Tc complexes has been accomplished by HPLC comparison with the Re congeners (Re1-Re8), which were synthesized at the macroscopic level and fully characterized by common analytical techniques. The biological evaluation of the 99m Tc(I) complexes comprised the determination of their in vitro binding to synthetic melanin, measurement of cellular uptake in B16F1 murine melanoma cells, as well as biodistribution studies in B16F1 melanoma-bearing mice. All the tested complexes have shown a moderate to high in vitro affinity to melanin, with percentages of binding spanning between 60 and 94%. In agreement with the poor cellular uptake measured in vitro, the in vivo tumor uptake of the complexes was in general relatively low, ranging between 0.12 and 1.69% ID g À1 at 4 h p.i. However, some complexes have shown favorable tumor-to-organ ratios with values as high as 28 and 5.3 for tumor-muscle and tumor-blood ratios, respectively. This seems to indicate that some selectivity towards melanoma tissue was conserved, and encourages further optimization of the in vitro/in vivo biological properties of this type of complexes aimed at finding novel radioactive probes for non-invasive imaging of melanoma.

The novel pyrazolyl-based ligands 3,5-Me2pz(CH2)2NH(CH2)2NH(CH2)2NH2 and pz*(CH2)2NH-Gly-CH2STrit (pz*=pz, 3,5-Me2pz, 4-(EtOOC)CH(2)-3,5-Me2pz) were synthesized, and their suitability to stabilize Re(V) oxocomplexes was evaluated using different starting materials, namely (NBu4)[ReOCl4], [ReOCl3(PPh3)2] and trans-[ReO2(py)4]Cl. Compound reacts with trans-[ReO2(py)4]Cl yielding the cationic compound [ReO(OMe){3,5-Me2pz(CH2)2N(CH2)2NH(CH2)2NH2}](BPh4) in a low isolated yield. In contrast, the neutral complexes [ReO{pz*(CH2)2NH-Gly-CH2S}] (pz*=pz, 3,5-Me2pz, 4-(EtOOCCH2)-3,5-Me2pz) were synthesized almost quantitatively by reacting [ReOCl3(PPh3)2] or (NBu4)[ReOCl4] with the trityl-protected chelators. The X-ray diffraction analysis of and confirmed the tetradentate coordination mode of the respective ancillary ligands. In the monoanionic chelator coordinates to the metal through four nitrogen atoms, while in the chelator is trianionic, coordinating to the metal through three nitrogens and one sulfur atom. Solution NMR studies of , including two-dimensional NMR techniques (1H COSY and 1H/13C HSQC), confirmed that the N3S coordination mode of the chelators is retained in solution. Unlike , complexes may be considered relevant in the development of radiopharmaceuticals, as further corroborated by the synthesis of the congener [99mTcO{pz(CH2)2-NH-Gly-CH2S}]. This radioactive compound was obtained from 99mTcO4- in aqueous medium, in almost quantitative yield and with high specific activity and radiochemical purity.

Complex fac-[Re(kappa(3)-H(mu-H)(2)B(tim(Me)))(CO)(3)] (1) reacts with protic azoles, like 2-mercapto-1-methylimidazole (tim(Me)H), 2-mercaptobenzothiazole (bztH), or pyrazoles (pz*H), to afford fac-[Re(kappa(3)-H(mu-H)B(tim(Me))(2)(CO)(3)] (2), fac-[Re(kappa(3)-H(mu-H)B(tim(Me))(bzt))(CO)(3)] (3), fac-[Re(kappa(3)-H(mu-H)B(tim(Me))(pz))(CO)(3)] (4), fac-[Re(kappa(3)-HB(tim(Me))(pz)(2))(CO)(3)] (5), and fac-[Re(kappa(3)-H(mu-H)B(tim(Me))(3,5-Me(2)-4-EtOOCCH(2)pz))(CO)(3)] (6). Complexes 2-6 are stabilized by tridentate poly(azolyl)borates generated in situ, and their formation involves most probably a metal-assisted process which is considerably faster for the pyrazole derivatives. The characterization of the novel complexes, 3-6, has been done by common analytical techniques, including single crystal X-ray diffraction analysis. The solid state structures confirmed the presence of hybrid heteroscopionates, presenting (kappa(3)-H, S, S'), (kappa(3)-H, S, N), or (kappa(3)-S, N, N) binding motifs. Multinuclear ((1)H, (13)C, and (11)B) NMR studies have also shown that the coordination mode found in the solid state is retained in solution.

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