In vivo validation of a Pb203-SPECT imaging probe for image-guided alpha particle therapy for metastatic melanoma.

Objectives Metastatic melanoma is one of the fastest growing cancer incidences in the world today. While disease detected early can be cured by surgery, metastatic melanoma is lethal because resistance develops rapidly to all approved therapies (5 year survival < 5%). One pervasive characteristic of melanoma cells relative to most normal cells is upregulation of glucose transporters (GLUT). While F-18 FDG is an appropriate imaging agent that exploits this difference for melanoma, a suitable therapy that is based on this targeting approach has yet to achieve clinical success. Our objective was to evaluate the potential of two [Pb203]-labeled glucosamine-based ligands (DOTA-BNCO-GC and TCMC-GC) that target glucose transporters (GLUTs) for [Pb203]/[Pb212]-image-guided radionuclide-based therapy for melanoma. The [Pb203]-SPECT imaging of GLUT can potentially allow for selection of patients for whom [Pb212]-therapy will be beneficial.

Methods DOTA- and TCMC-conjugated glucosamines were synthesized as we described previously.[1] Receptor-mediated accumulation of each agent in melanoma cells was confirmed in previous cellular uptake studies (B16 cells). For this study, melanoma tumor-bearing mice (B16 cells) were injected (IV) with 3.7 MBq of [Pb203]DOTA-BNCO-GC and [Pb203]TCMC-GC glycoconjugates (10ug). Biodistribution studies were completed at 30min, 1h and 4h by routine methods described previously.[2]

Results The Pb203-labeled glycoconjugates were observed to accumulate rapidly in tumors with primarily renal clearance. Slightly more rapid tumor accumulation was observed for the [Pb203]TCMC-GC conjugate in the first 30min post-injection (5.67%±2.76 ID/g) relative to the [Pb203]DOTA-BNCO-GC glycoconjugate (3.55% ±0.04 ID/g). On the other hand, [Pb203]TCMC-GC appeared to wash out from the tumor faster than the [Pb203]DOTA-BNCO-GC conjugate. The tumor retention of [203Pb]TCMC-GC and [Pb203]DOTA-BNCO-GC were respectively 2.15%±0.84 ID/g and 1.22%±0.178 ID/g at 4h post- injection. Both agents were cleared through the kidneys with limited/no accumulation in other organs.

Conclusions Pb203-labeled glucosamine derivatives, DOTA-BNCO-GC and TCMC-GC, displayed rapid tumor accumulation and retention relative to normal tissues, with primarily renal clearance and little to no observed accumulation in other organs (tumor-to-muscle ratio was > 15 for both BNCO-GC and TCMC-GC at 4 post-injection). These results support hypothesis that [Pb203]-glucosamine conjugates that target GLUTs can potentially serve as SPECT imaging agents for image guided [Pb212]-labeled therapy.