[Tc-99m]oxotechnetium(V) complexes of amine-amide-dithiol chelates with dialkylaminoalkyl substituents as potential diagnostic probes for malignant melanoma

[Tc-99m]oxotechnetium(V) complexes of amine-amide-dithiol (AADT) chelates c ontaining tertiary amine substituents were synthesized and shown to have af finity for melanoma. For complexation the AADT-CH2[CH2](n)NR2 (n = 1, 2; R = Et, n-Bu) ligand was mixed with a [Tc-99m]oxotechnetium(V)-glucoheptonate precursor to make the AADT-[Tc-99m]oxotechnetium(V) complexes in nearly qu antitative yield. Structurally analogous nonradioactive oxorhenium(V) compl exes were also synthesized and characterized. In vitro sigma -receptor affi nity measurements indicate these complexes to possess a-affinity in the low micromolar range with K-i values in the 7.8-26.1 and 0.18-2.3 muM range fo r the sigma (1)- and sigma (2)-receptors, respectively. In vitro cell uptak e of the Tc-99m 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 C57B1/B16 mouse melanoma model demonstrated significant tumo r localization. Complex I-Tc (n = 1, R = Et) displayed an in vivo tumor upt ake 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 adminis tration with M/B, M/S, and M/L ratios >2, a greater tumor retention and sli ghtly 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 tu mor uptake and significant tumor/nontumor ratios indicate that such small t echnetium-99m-based molecular probes can be developed as in vivo diagnostic agents for melanoma and its metastases.