Validation of a novel CHX-A '' derivative suitable for peptide conjugation: Small animal PET/CT imaging using yttrium-86-CHX-A ''-octreotide

Washington University in St. Louis, San Luis, Missouri, United States
Journal of Medicinal Chemistry (Impact Factor: 5.45). 08/2006; 49(14):4297-304. DOI: 10.1021/jm060317v
Source: PubMed


A versatile bifunctional chelating reagent based on a preorganized cyclohexyl derivative of DTPA (CHX-A'') has been developed for the convenient N-terminal labeling of peptides with metal ion radionuclides of Bi(III), In(III), Lu(III), or Y(III). This was achieved via the synthesis of a mono-N-hydroxysuccinimidyl penta-tert-butyl ester derivative of CHX-A'' (trans-cyclohexyldiethylenetriaminepenta-acetic acid) featuring a glutaric acid spacer. Commercially obtained octreotide was modified at its N-terminus by this reagent in the solution phase, and its subsequent radiolabeling with (111)In (T(1/2) = 2.8 d) and (86)Y (T(1/2) = 14.7 h) demonstrated. Small animal PET/CT imaging results of (86)Y-CHX-A''-octreotide in a somatostatin receptor-positive tumor-bearing rat model are presented for the validation of the novel agent.

1 Follower
4 Reads
  • Source
    • "The CHX- A " bifunctional chelator has been used successfully to radiolabel antibodies and peptides with a number of radionuclides including, 213 Bi [28] 212 Bi [29], 90 Y [30] [31], 177 Lu [32] and 111 In [31]. Recently, a novel protected version of the CHX-A " chelator was described that was suitable for solid-phase peptide synthesis [33]. A mono-N-hydroxysuccinimidyl penta-tertbutyl ester derivative of CHX-A " with a glutaric acid spacer enabled efficient coupling to peptides immobilized on solid supports or in solution. "
    [Show abstract] [Hide abstract]
    ABSTRACT: A novel alpha-melanocyte-stimulating hormone peptide analog CHX-A''-Re(Arg(11))CCMSH, which targeted the melanocortin-1 receptor (MC1-R) overexpressed on melanoma cells, was investigated for its biodistribution and tumor imaging properties. The metal bifunctional chelator CHX-A'' was conjugated to the melanoma targeting peptide (Arg(11))CCMSH and cyclized by Re incorporation to yield CHX-A''-Re(Arg(11))CCMSH. CHX-A''-Re(Arg(11))CCMSH was labeled with (111)In, (86)Y and (68)Ga, and the radiolabeled peptides were examined in B16/F1 melanoma-bearing mice for their pharmacokinetic as well as their tumor targeting properties using small animal SPECT and PET. The radiolabeling efficiencies of the (111)In-, (86)Y- and (68)Ga-labeled CHX-A''-Re(Arg(11))CCMSH peptides were >95%, resulting in specific activities of 4.44, 3.7 and 1.85 MBq/microg, respectively. Tumor uptake of the (111)In-, (86)Y- and (68)Ga-labeled peptides was rapid with 4.17+/-0.94, 4.68+/-1.02 and 2.68+/-0.69 %ID/g present in the tumors 2 h postinjection, respectively. Disappearance of radioactivity from the normal organs and tissues was rapid with the exception of the kidneys. Melanoma tumors were imaged with all three radiolabeled peptides 2 h postinjection. MC1-R-specific uptake was confirmed by competitive receptor blocking studies. Melanoma tumor uptake and imaging was exhibited by the (111)In-, (86)Y- and (68)Ga-labeled Re(Arg(11))CCMSH peptides, although the tumor uptake was moderated by low specific activity. The facile radiolabeling properties of CHX-A''-Re(Arg(11))CCMSH allow it to be employed as a melanoma imaging agent with little or no purification after (111)In, (86)Y and (68)Ga labeling.
    Nuclear Medicine and Biology 05/2009; 36(4):345-54. DOI:10.1016/j.nucmedbio.2009.01.007 · 2.41 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Generator-produced positron emission tomography tracers have gained much attention recently due to favorable imaging characteristics, accessibility and affordability. The focus of this study was to design and validate a semiautomated module for 68Ga-labeled chemistry utilizing infrared-based heating for rapid control of thermal cycle. A prototype module was built and installed in our laboratory. DOTA (1,4,7,10-tetra-azacyclododecane-1,4,7,10-tetra-acetic acid) was manually labeled (10-1000 nmol) with 68Ga to optimize synthesis conditions. For automation, 250 nmol of DOTA was labeled with 68Ga with reaction times of 5 min (n=5), 10 min (n=5) and 20 min (n=6). A dose calibrator and radio-thin-layer chromatography were used to access the product yield and quality of both manual and automated syntheses. A semiautomated 68Ga synthesis module was developed. The system showed that software control could be used to drive a multistep radiochemical synthesis and to produce 68Ga-DOTA with >95% radiochemical purity, similar to that in manual synthesis. The device also showed that for a short reaction time of 5 min, decay-corrected radioactive yields of >70% could be achieved. The total synthesis was as short as 22 min, including 6-8 min for HCl evaporation. The temperature and pressure profiles of the process were consistent. We demonstrated the use of a commercially available 68Ga/68Ge generator with a semiautomated module to successfully label the bifunctional chelator DOTA with 68Ga. Further investigation with different 68Ga-labeled bioconjugates is warranted to demonstrate the usefulness of the module as a tool for tracer development and imaging research.
    Nuclear Medicine and Biology 02/2007; 34(1):121-7. DOI:10.1016/j.nucmedbio.2006.10.011 · 2.41 Impact Factor
  • European journal of nuclear medicine and molecular imaging 03/2007; 34(2):294-300. DOI:10.1007/s00259-006-0330-0 · 5.38 Impact Factor
Show more