Synthesis of tripeptide derivatized cyclopentadienyl complexes of technetium and rhenium as radiopharmaceutical probes.

We describe the syntheses of half-sandwich complexes of the type [(η(5)-Cp(CONH-R))M(CO)3] with M = Re or (99m)Tc. The R group represents different tri-peptides (tpe) which display high binding affinities for oligopeptide transporters PEPT2. The (99m)Tc complexes were prepared directly from [(99m)Tc(OH2)3(CO)3](+) and Diels-Alder dimerized, cyclopentadienyl derivatized peptides in water. This approach corroborates the feasibility of metal-mediated retro Diels-Alder reactions for the preparation of not only small molecules but also peptides carrying a [(η(5)-Cp)(99m)Tc(CO)3] tag. We synthesized the Diels-Alder product [(HCpCONH-tpe)2] from Thiele's acid [(η(5)-HCpCOOH)2] via double peptide coupling. The Re-complexes [(η(5)-CpCONH-tpe)Re(CO)3] were obtained by attaching [(Cp-COOH)Re(CO)3] directly to the N-terminus of peptides as received from SPPS. The authenticity of the (99m)Tc-complexes is confirmed by chromatographic comparison with the corresponding rhenium complexes, fully characterized by spectroscopic techniques.

[(Cp-R)M(CO)3] (M = Re or 99mTc) conjugates for theranostic receptor targeting.

Cyclopentadienyl complexes of 99mTc became accessible via a retro Diels-Alder synthetic approach of dimerized cyclopentadiene derivatives. So far, this approach was limited to derivatives comprising a carboxylic acid group, directly conjugated to the Cp-ring, leading to complexes [(C5H5COOH)99mTc(CO)3] and [(C5H5CONH-R)99mTc(CO)3], respectively. The introduction of an -NCO group via Curtius rearrangement and subsequent in situ reactions with alcohols or amines gave [(C5H5NHCO-OR)2] and [(C5H5NHCO-NHR)2]. To increase the spacer lengths between the Cp-ring and the functional groups, methylene and ethylene spacers were introduced to yield C5H5-CH2COOH and C5H5-C2H4COOH respectively. The latter Cp-derivatives reacted with [99mTcO4)]- and in the presence of CO releasing/reducing agents to the corresponding [(C5H5-spacer-COOH)99mTc(CO)3] complexes. The carboxylato groups can be derivatized with targeting functions, leading to structurally altered receptor binding complexes, with 99mTc for imaging and with rhenium for therapy. The nature of the 99mTc complexes was assessed by HPLC comparison with the corresponding rhenium compounds.

The [(Cp)M(CO)(3)] (M=Re, (99m)Tc) building block for imaging agents and bioinorganic probes: perspectives and limitations.

Starting from asymmetric Thiele's acid derivatives, two different imaging probes [(99m)Tc(CO)(3)(CpR)] (R=potential targeting vector) are generated simultaneously in one-pot and from one substrate. This extends the previously introduced labeling strategy of metal-mediated retro-Diels-Alder reaction with HCp-R dimers. We demonstrate that chemically active functionalities such as hydroxamic acids are not following this labeling strategy. Adopting the principle of replacing phenyl rings by [Re(CO)(3)(Cp)] entities, potent histone deacetylase (HDAC)-inhibiting Re analogs of suberoylanlilide hydroxamic acid (SAHA; N-hydroxy-N'-phenyloctanediamide) were synthesized and characterized. Cytotoxic evaluation on different tumor cell lines revealed low IC(50) values [µM] for these compounds, comparable to their purely organic congeners.

[(Cp-R)M(CO)3] (M=Re or 99mTc) Arylsulfonamide, arylsulfamide, and arylsulfamate conjugates for selective targeting of human carbonic anhydrase IX.

Enhanced receptor selectivity: carbonic anhydrase inhibitors are relevant for both cancer diagnosis and therapy. Combining non-radioactive Re compounds with their radioactive (99m)Tc homologs enables the use of identical molecules for therapy and imaging (theragnostic). The syntheses and in vitro evaluation of [(Cp-R)M(CO)(3)] (Cp=cyclopentadienyl, M=Re, (99m)Tc) with R being a highly potent carbonic-anhydrase-targeting vector is reported.

Preparation and biological evaluation of cyclopentadienyl-based 99mTc-complexes [(Cp-R)99mTc(CO)3] mimicking benzamides for malignant melanoma targeting.

The biological evaluation of half-sandwich (99m)Tc-complexes that surrogate iodobenzamide with a high affinity for melanin tumor tissue is described. We have synthesized via retro Diels-Alder reaction two models of (99m)Tc complexes which possess the piano stool [Cp(99m)Tc(CO)(3)] motif instead of a phenyl ring as in the original iodobenzamide (123)I-N-(N-benzylpiperidin-4-yl)-2-iodobenzamide (2-IBP) and N-(2-diethylaminoethyl)-4-iodobenzamide (BZA). Diels-Alder products 2a-b (HCp-CONHR)(2) (2a, R=2-diethylaminoethyl; 2b, R=benzylpiperidin-4-yl) were prepared and reacted with fac-[(99m)Tc(H(2)O)(3)(CO)(3))](+) 1 in water to produce the corresponding (99m)Tc complexes [(2a)(99m)Tc(CO)(3))] 4a and [(2b)(99m)Tc(CO)(3))] 4b. The structures of the (99m)Tc complexes on the no-carrier-added level have been confirmed by chromatographic comparison with the corresponding rhenium complexes 3a and 3b, macroscopically characterized by IR, NMR, ESI-MS and X-ray crystallography for 3a [triclinic, P-1, a=7.3518(1) A, b=8.0309(2) A, c=17.5536(3) A, alpha=99.1260(5) degrees, beta=90.4215(14) degree , gamma=117.0187(11) degrees]. The radioconjugate 4b showed good in vitro stability. In murine melanoma B16F1 cells, significant cellular uptake (43.9% of the total applied activity) was attained after 4 h at 37 degrees C with about 50% of the cell-associated radioactivity being internalized in the cells (22% of the applied activity). Furthermore, in melanoma-bearing C57BL6 mice, tumor uptake values of 3.39+/-0.50 %ID g(-1) and 3.21+/-0.26 %ID g(-1) at 1 and 4 h postinjection, respectively, were observed indicating a good retention of 4b in the tumor.