7 research outputs found
Synthesis and evaluation of 18F-labeled carbonic anhydrase IX inhibitors for imaging with positron emission tomography
Two carbonic anhydrase IX (CA IX) inhibitors were radiolabeled with (18)F, and evaluated for imaging CA IX expression. Despite good affinity for CA IX and excellent plasma stability, uptake of both tracers in CA IX-expressing HT-29 tumor xenografts in mice was low. (18)F-FEC accumulated predominately in the liver and nasal cavity, whereas a significant amount of (18)F-U-104 was retained in blood. Due to minimal uptake in HT-29 tumors compared to other organs/tissues, these two tracers are not suitable for use for CA IX-targeted imaging
Evaluation of agonist and antagonist radioligands for somatostatin receptor imaging of breast cancer using positron emission tomography
Background:
The somatostatin receptor subtype 2 (sstr2) is expressed on a majority of luminal breast cancers, however SPECT and scintigraphy imaging with agonistic sstr2 probes has been sub-optimal. High affinity antagonists can access more binding sites on the cell surface, resulting in higher tumor uptake and improved sensitivity. We compared the tumor uptake and biodistribution of the antagonist 68Ga-NODAGA-JR11 with two agonists 68Ga-DOTA-Tyr3-octreotide (68Ga-DOTATOC) and 68Ga-DOTA-Tyr3-octreotate (68Ga-DOTATATE), in the human, sstr2-positive, luminal breast cancer model: ZR-75-1.
Results:
Peptides were assayed for binding affinity using a filtration-based competitive assay to sstr2. natGa-DOTATOC and natGa-DOTATATE had excellent affinity (inhibition constant Ki: 0.9 ± 0.1 nM and 1.4 ± 0.3 nM respectively) compared to natGa-NODAGA-JR11 (25.9 ± 0.2 nM). The number of binding sites on ZR-75-1 cells was determined in vitro by saturation assays. Agonist 67/natGa-DOTATOC bound to 6.64 ± 0.39 × 104 sites/cells, which was 1.5-fold higher than 67/natGa-NODAGA-JR11 and 2.3-fold higher than 67/natGa-DOTATATE. All three 68Ga-labeled peptides were obtained in good decay-corrected radiochemical yield (61-68%) and were purified by high performance liquid chromatography to ensure high specific activity (137 – 281 MBq/nmol at the end of synthesis). NOD scid gamma mice bearing ZR-75-1 tumors were injected intravenously with the labeled peptides and used for PET/CT imaging and biodistribution at 1 h post-injection. We found that 68Ga-DOTATOC had the highest tumor uptake (18.4 ± 2.9%ID/g), followed by 68Ga-DOTATATE (15.2 ± 2.2%ID/g) and 68Ga-NODAGA-JR11 (12.2 ± 0.8%ID/g). Tumor-to-blood and tumor-to-muscle ratios were also higher for the agonists (>40 and >150 respectively), compared to the antagonist (15.6 ± 2.2 and 45.2 ± 11.6 respectively).
Conclusions:
The antagonist 68Ga-NODAGA-JR11 had the lowest tumor uptake and contrast compared to agonists 68Ga-DOTATOC and 68Ga-DOTATATE in ZR-75-1 xenografts.
The main contributing factor to this result could be the use of an endogenously expressing cell line, which may differ from previously published transfected models in the number of low-affinity, antagonist-specific binding sites. The relative merit of agonists versus antagonists for sstr2 breast cancer imaging warrants further investigation, first in preclinical models with other sstr2-positive breast cancer xenografts, and ultimately in luminal breast cancer patients.Medicine, Faculty ofNon UBCRadiology, Department ofReviewedFacult
Imaging Bradykinin B1 Receptor with <sup>68</sup>Ga-Labeled [des-Arg<sup>10</sup>]Kallidin Derivatives: Effect of the Linker on Biodistribution and Tumor Uptake
Bradykinin
B1 receptor (B1R) that is overexpressed in cancers but
minimally expressed in normal healthy tissues represents an attractive
biomarker for the development of cancer imaging agents. The goal of
this study was to evaluate the effect of different linkers on the
pharmacokinetics and tumor uptake of a B1R-targeting radio-peptide
sequence, <sup>68</sup>Ga-DOTA-linker-Lys-Arg-Pro-Hyp-Gly-Cha-Ser-Pro-Leu.
Four peptides, SH01078, P03034, P04115, and P04168, with 6-aminohexanoic
acid, 9-amino-4,7-dioxanonanoic acid, Gly-Gly, and 4-amino-(1-carboxymethyl)piperidine,
respectively, as the linker were synthesized and evaluated. In vitro
competition binding assays showed that the <i>K</i><sub>i</sub> values of SH01078, P03034, P04115, and P04168 were 27.8 ±
4.9, 16.0 ± 1.9, 11.4 ± 2.5, and 3.6 ± 0.2 nM, respectively.
Imaging and biodistribution studies were performed in mice bearing
both B1R-positive HEK293T::hB1R and B1R-negative HEK293T tumors. All
tracers showed mainly renal excretion with excellent tumor visualization
and minimal background activity except for kidneys and bladder. The
average uptake of <sup>68</sup>Ga-labeled SH01078, P03034, and P04115
in HEK293T::hB1R tumor was similar (1.96–2.17%ID/g) at 1 h
postinjection. <sup>68</sup>Ga-P04168 generated higher HEK293T::hB1R
tumor uptake (4.15
± 1.13%ID/g) and lower background activity, leading to a >2-fold
improvement in HEK293T::hB1R tumor-to-background (HEK293T tumor,
blood, muscle, and liver) contrasts over those of <sup>68</sup>Ga-labeled
SH01078, P03034, and P04115. Our results indicate that the choice
of linker affects binding affinity, pharmacokinetics, and tumor targeting.
The use of the cationic 4-amino-(1-carboxymethyl)piperidine linker
improved tumor visualization, and the resulting <sup>68</sup>Ga-P04168
might be promising for clinical application for imaging B1R-expressing
tumors with positron emission tomography
Synthesis and evaluation of 18
Two carbonic anhydrase IX (CA IX) inhibitors were radiolabeled with (18)F, and evaluated for imaging CA IX expression. Despite good affinity for CA IX and excellent plasma stability, uptake of both tracers in CA IX-expressing HT-29 tumor xenografts in mice was low. (18)F-FEC accumulated predominately in the liver and nasal cavity, whereas a significant amount of (18)F-U-104 was retained in blood. Due to minimal uptake in HT-29 tumors compared to other organs/tissues, these two tracers are not suitable for use for CA IX-targeted imaging