TY - JOUR
T1 - 67Ga-labeled deferoxamine derivatives for imaging bacterial infection
T2 - Preparation and screening of functionalized siderophore complexes
AU - Ioppolo, Joseph A.
AU - Caldwell, Deanna
AU - Beiraghi, Omid
AU - Llano, Lisset
AU - Blacker, Megan
AU - Valliant, John F.
AU - Berti, Paul J.
PY - 2017/9
Y1 - 2017/9
N2 - Introduction Deferoxamine (DFO) is a siderophore that bacteria use to scavenge iron and could serve as a targeting vector to image bacterial infection where current techniques have critical limitations. [67Ga]-DFO, which is a mimetic of the corresponding iron complex, is taken up by bacteria in culture, however in vivo it clears too rapidly to allow for imaging of infection. In response, we developed several new DFO derivatives to identify those that accumulate in bacteria, and at sites of infection, and that could potentially have improved pharmacokinetics. Methods A library of DFO derivatives was synthesized by functionalizing the terminal amine group of DFO using three different carbamate-forming reactions. Uptake of [67Ga]-DFO and the 67Ga-labeled derivatives by bacteria and the biodistribution of lead compounds were studied. Results 67Ga-labeled DFO derivatives were prepared and isolated in >90% radiochemical yield and >95% radiochemical purity. The derivatives had significant but slower uptake rates in Staphylococcus aureus than [67Ga]-DFO (6% to 60% of the control rate), with no uptake for the most lipophilic derivatives. Biodistribution studies in mice with a S. aureus infection in one thigh revealed that the ethyl carbamate derivative had an excellent infected-to-non-infected ratio (11:1), but high non-specific localization in the gall bladder, liver and small intestine. Conclusions The work reported shows that it is possible to functionalize DFO-type siderophores and retain active uptake of the 67Ga-labeled complexes by bacteria. Novel 67Ga-labeled DFO derivatives were specifically taken up by S. aureus and selected derivatives demonstrated in vivo localization at sites of infection. Advances in knowledge and implications for patient care 67Ga-labeled DFO derivatives were actively transported by bacteria using the iron-siderophore pathway, suggesting that it is possible to develop siderophore-based radiopharmaceuticals for imaging bacterial infection.
AB - Introduction Deferoxamine (DFO) is a siderophore that bacteria use to scavenge iron and could serve as a targeting vector to image bacterial infection where current techniques have critical limitations. [67Ga]-DFO, which is a mimetic of the corresponding iron complex, is taken up by bacteria in culture, however in vivo it clears too rapidly to allow for imaging of infection. In response, we developed several new DFO derivatives to identify those that accumulate in bacteria, and at sites of infection, and that could potentially have improved pharmacokinetics. Methods A library of DFO derivatives was synthesized by functionalizing the terminal amine group of DFO using three different carbamate-forming reactions. Uptake of [67Ga]-DFO and the 67Ga-labeled derivatives by bacteria and the biodistribution of lead compounds were studied. Results 67Ga-labeled DFO derivatives were prepared and isolated in >90% radiochemical yield and >95% radiochemical purity. The derivatives had significant but slower uptake rates in Staphylococcus aureus than [67Ga]-DFO (6% to 60% of the control rate), with no uptake for the most lipophilic derivatives. Biodistribution studies in mice with a S. aureus infection in one thigh revealed that the ethyl carbamate derivative had an excellent infected-to-non-infected ratio (11:1), but high non-specific localization in the gall bladder, liver and small intestine. Conclusions The work reported shows that it is possible to functionalize DFO-type siderophores and retain active uptake of the 67Ga-labeled complexes by bacteria. Novel 67Ga-labeled DFO derivatives were specifically taken up by S. aureus and selected derivatives demonstrated in vivo localization at sites of infection. Advances in knowledge and implications for patient care 67Ga-labeled DFO derivatives were actively transported by bacteria using the iron-siderophore pathway, suggesting that it is possible to develop siderophore-based radiopharmaceuticals for imaging bacterial infection.
KW - Bacterial infection
KW - Deferoxamine
KW - Gallium-67
KW - Imaging
KW - Siderophore
KW - SPECT
UR - http://www.scopus.com/inward/record.url?scp=85020284347&partnerID=8YFLogxK
U2 - 10.1016/j.nucmedbio.2017.05.010
DO - 10.1016/j.nucmedbio.2017.05.010
M3 - Article
C2 - 28602965
AN - SCOPUS:85020284347
SN - 0969-8051
VL - 52
SP - 32
EP - 41
JO - Nuclear Medicine and Biology
JF - Nuclear Medicine and Biology
ER -