title: [99mTc]oxotechnetium(V) complexes amine-amide-dithiol chelates with dialkylaminoalkyl substituents as potential diagnostic probes for malignant melanoma.
abstract: [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]nNR2 (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 sigma-receptor affinity measurements indicate these complexes to possess sigma-affinity in the low micromolar range with K(i) values in the 7.8-26.1 and 0.18-2.3 microM range for the sigma1- and sigma2-receptors, respectively. In vitro cell uptake of the 99mTc complexes in intact B16 murine melanoma cells at 37 degrees 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.
authors.affiliation: Department of Radiology, Harvard Medical School and Brigham and Women's Hospital, Boston, Massachusetts 02115, USA.
authors.forename: M
authors.initials: M
authors.lastname: Friebe
authors.forename: A
authors.initials: A
authors.lastname: Mahmood
authors.forename: C
authors.initials: C
authors.lastname: Bolzati
authors.forename: A
authors.initials: A
authors.lastname: Drews
authors.forename: B
authors.initials: B
authors.lastname: Johannsen
authors.forename: M
authors.initials: M
authors.lastname: Eisenhut
authors.forename: D
authors.initials: D
authors.lastname: Kraemer
authors.forename: A
authors.initials: A
authors.lastname: Davison
authors.forename: A G
authors.initials: AG
authors.lastname: Jones
mesh_terms: D000818:Animals; D001667:Binding, Competitive; D001921:Brain / Q000378:metabolism; D002614:Chelating Agents / Q000138:chemical synthesis* / Q000737:chemistry; D018360:Crystallography, X-Ray; D006168:Guinea Pigs; D006801:Humans; D066298:In Vitro Techniques; D008546:Melanoma, Experimental / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D009368:Neoplasm Transplantation; D015609:Organotechnetium Compounds / Q000138:chemical synthesis* / Q000737:chemistry / Q000493:pharmacokinetics; D011869:Radioligand Assay; D017480:Receptors, sigma / Q000378:metabolism; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D013438:Sulfhydryl Compounds / Q000138:chemical synthesis* / Q000737:chemistry; D014018:Tissue Distribution; D014407:Tumor Cells, Cultured
chemical_list: D002614:Chelating Agents; D015609:Organotechnetium Compounds; D017480:Receptors, sigma; D013438:Sulfhydryl Compounds