Biodistribution and imaging of an hsp90 ligand labelled with (111)In and (67)Ga for imaging of cell death

BACKGROUND: 4-(N-(S-glutathionylacetyl)amino) phenylarsonous acid (GSAO) when conjugated at the γ-glutamyl residue with fluorophores and radio-isotopes is able to image dead and dying cells in vitro and in vivo by binding to intracellular 90-kDa heat shock proteins (hsp90) when cell membrane integrity is compromised. The ability to image cell death has potential clinical impact especially for early treatment response assessment in oncology. This work aims to assess the biodistribution and tumour uptake of diethylene triamine pentaacetic acid GSAO labelled with (111)In ([(111)In]In-DTPA-GSAO) and 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid GSAO labelled with (67)Ga ([(67)Ga]Ga-DOTA-GSAO) in a murine subcutaneous tumour xenograft model and estimate dosimetry of [(67)Ga]Ga-DOTA-GSAO. RESULTS: There was good tumour uptake of both [(111)In]In-DTPA-GSAO and [(67)Ga]Ga-DOTA-GSAO (2.44 ± 0.26% injected activity per gramme of tissue (%IA/g) and 2.75 ± 0.34 %IA/g, respectively) in Balb c nu/nu mice bearing subcutaneous tumour xenografts of a human metastatic prostate cancer cell line (PC3M-luc-c6). Peak tumour uptake occurred at 2.7 h post injection. [(111)In]In-DTPA-GSAO and [(67)Ga]Ga-DOTA-GSAO demonstrated increased uptake in the liver (4.40 ± 0.86 %IA/g and 1.72 ± 0.27 %IA/g, respectively), kidneys (16.54 ± 3.86 %IA/g and 8.16 ± 1.33 %IA/g) and spleen (6.44 ± 1.24 %IA/g and 1.85 ± 0.44 %IA/g); however, uptake in these organs was significantly lower with [(67)Ga]Ga-DOTA-GSAO (p = 0.006, p = 0.017 and p = 0.003, respectively). Uptake of [(67)Ga]Ga-DOTA-GSAO into tumour was higher than all organs except the kidneys. There was negligible uptake in the other organs. Excretion of [(67)Ga]Ga-DOTA-GSAO was more rapid than [(111)In]In-DTPA-GSAO. Estimated effective dose of [(67)Ga]Ga-DOTA-GSAO for an adult male human was 1.54 × 10(− 2) mSv/MBq. CONCLUSIONS: [(67)Ga]Ga-DOTA-GSAO demonstrates higher specific uptake in dead and dying cells within tumours and lower uptake in normal organs than [(111)In]In-DTPA-GSAO. [(67)Ga]Ga-DOTA-GSAO may be potentially useful for imaging cell death in vivo. Dosimetry estimates for [(67)Ga]Ga-DOTA-GSAO are acceptable for future human studies. This work also prepares for development of (68)Ga GSAO radiopharmaceuticals.