[99mTc]Oxotechnetium(V) Complexes of Amine-Amide-Dithiol Chelates with Dialkylaminoalkyl Substituents as Potential Diagnostic Probes for Malignant Melanoma

• Published in: Journal of medicinal chemistry Vol. 44; no. 19; pp. 3132 - 3140
• Main Authors: Friebe, Matthias, Mahmood, Ashfaq, Bolzati, Cristina, Drews, Antje, Johannsen, Bernd, Eisenhut, Michael, Kraemer, Daniel, Davison, Alan, Jones, Alun G
• Format: Journal Article
• Language: English
• Published: WASHINGTON American Chemical Society 13.09.2001; Amer Chemical Soc
• Subjects: Animals; Binding, Competitive; Biological and medical sciences; Brain - metabolism; Chelating Agents - chemical synthesis; Chelating Agents - chemistry; Chemistry, Medicinal; Contrast media. Radiopharmaceuticals; Crystallography, X-Ray; Guinea Pigs; Humans; In Vitro Techniques; Life Sciences & Biomedicine; Medical sciences; Melanoma, Experimental - metabolism; Mice; Mice, Inbred C57BL; Neoplasm Transplantation; Organotechnetium Compounds - chemical synthesis; Organotechnetium Compounds - chemistry; Organotechnetium Compounds - pharmacokinetics; Pharmacology & Pharmacy; Pharmacology. Drug treatments; Radioligand Assay; Receptors, sigma - metabolism; Science & Technology; Stereoisomerism; Structure-Activity Relationship; Sulfhydryl Compounds - chemical synthesis; Sulfhydryl Compounds - chemistry; Tissue Distribution; Tumor Cells, Cultured; IN-VITRO; RADIOPHARMACEUTICALS; AFFINITY; BIODISTRIBUTION; TECHNETIUM(V); LIGAND; TC-99M COMPLEXES; RECEPTORS; BINDING; DERIVATIVES; Intravenous administration; Ligand; Thiolate; Sigma receptor; Dissociation constant; Lipophily; Technetium Isotopes; Technetium V Complexes; Rhenium V Complexes; Tissue; Structure activity relation; B16-Melanoma; Diagnosis; Mammary gland; Radiopharmaceuticals; Chemical synthesis; Tumor cell; Human; Aminoamide; Organic ligand; Transition metal Complexes; Malignant tumor; X ray diffraction; In vitro; Uptake; Oxo complex; Diagnostic agent; In vivo; Biological fixation; Cell line; Animal; Distribution; Affinity; Carboxamide; Aminothiol; Pharmacokinetics; Physicochemical properties; Crystalline structure
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm0005407

[99mTc]oxotechnetium(V) complexes of amine-amide-dithiol (AADT) chelates containing tertiary amine substituents were synthesized and shown to have affinity for melanoma. For complexation the AADT−CH2[CH2] n NR2 (n = 1, 2; R = Et, n-Bu) ligand was mixed with a [99mTc]oxotechnetium(V)-glucoheptonate precursor to make the AADT−[99mTc]oxotechnetium(V) complexes in nearly quantitative yield. Structurally analogous nonradioactive oxorhenium(V) complexes were also synthesized and characterized. In vitro σ-receptor affinity measurements indicate these complexes to possess σ-affinity in the low micromolar range with K i values in the 7.8−26.1 and 0.18−2.3 μM range for the σ1- and σ2-receptors, respectively. In vitro cell uptake of the 99mTc complexes in intact B16 murine melanoma cells at 37 °C after a 60-min incubation ranged from 12% for complex 2 (n = 1, R = n-Bu) to 68% for complex 4 (n = 2, R = n-Bu). In vivo evaluation of complexes 1-Tc − 4-Tc in the C57Bl/B16 mouse melanoma model demonstrated significant tumor localization. Complex 1-Tc (n = 1, R = Et) displayed an in vivo tumor uptake of 7.6% ID/g at 1 h after administration with initial melanoma/blood (M/B), melanoma/spleen (M/S), and melanoma/lung (M/L) ratios >4; these ratios increased to 10.8, 10.1, and 7.3, respectively, at 6 h. While complex 3-Tc (n = 3, R = Et) had an initial tumor uptake of 3.7% ID/g 1 h after administration with M/B, M/S, and M/L ratios >2, a greater tumor retention and slightly faster clearance from nontumor-containing organs resulted in M/B, M/S, and M/L ratios of 19.1, 19.1, and 12.7, respectively, at 6 h. The high tumor uptake and significant tumor/nontumor ratios indicate that such small technetium-99m-based molecular probes can be developed as in vivo diagnostic agents for melanoma and its metastases.