Labeling with radiometals

Figure 6.7-9. Chemically reactive forms of two macrocyclic chelators that can be conjugated to monoclonal antibodies or peptides for labeling with radiometals. Groups for conjugation to the antibodies or peptides are shaded. BAD p-bromoacetamidobenzyl-DOTA complexes Ga, Lu, Pb, Bi or Ac. BAT bromoacetamidobenzyl-TETA complexes Cu or Cu.

BALTER, H.S., et al., DOTA-TATE alternative labellings with halogens and radiometals , Trends in Radiopharmaceuticals (Proc. Int. Symp. Vienna, 2005), IAEA, Vienna (2007). 

Platelets and white blood cells (WBC) can be labeled with In to provide agents for imaging inflammatory processes and thrombi (McAfee and Thakur 1976, Keeley and Hillis 1996, Becker and Meller 2001). A weak complex is formed between the In radiometal and 8-hydroxyquinoline (oxine). Since the hn-oxine complex is weak, the metal rapidly exchanges with transferrin in the plasma. In the absence of plasma, the complex diffuses across the cell membrane and the metal binds to intracellular sites. In humans, hn-labeledWBC will accumulate at sites of inflammation and also localize in the liver and spleen. 

A number of radioactive nuclides are commercially available. For use in organic and biochemical studies, a variety of labeled compounds are supphed. Some short-Kved tracers are supphed by generators (see Chap. 40 in Vol. 4). Detailed information is obtainable from catalogs or home pages of the companies or agencies producing or supplying radioactive nucKdes and labeled compounds. See Vol. 4 for customized synthesis of compounds labeled with H, i8p, Tc, radio-iodines, and radiometals. 

Interestingly, Desferrioxamine-B appeared to be of particular relevance for the complexation of tetra- and pentavalent radiometals. DFO-conjugated compounds such as DFO-succinyl-D-Phe-octreotide have been successfully labeled with the two longer-lived positron emitting radionuclides Zr (Meijs et al. 1992) and Nb (Busse et al. 1999). 

Antunes P, Ginj M, Zhang H et al. (2007) Are radiogallium-labeled DOTA-conjugated somatostatin analogs superior to those labeled with other radiometals Eur J Nucl Med Mol Imaging 34 982-993... 

Subramanian, R., and Meares, C.F. (1991) Bifunctional chelating agents for radiometal-labeled monoclonal antibodies. In Cancer Imaging with Radiolabeled Antibodies (D.M. Coldenberg, ed.), pp. 183-199. Kluwer, Boston, MA. 

None of the N2S2 or N3S systems described above is suitable for the postformed labeling of biomolecules (i.e. coupling a chelator to the biomolecule, followed by incorporation of the radiometal into the chelator) because the unfavorable kinetics of complexation or transchelation require relatively harsh conditions (strong acid/alkali, heat) which the biomolecule would not tolerate. In order to combine the advantages of in vivo stability in the amido systems with the better complexation... 

Heppeler A, Froidevaux S, Macke HR, et al. (1999) Radiometal-labeled macro-cyclic chelator-derivatised somatostatin analogue with superb tumor-targeting... 

There are two methods the preformed radiometal-chelate method and the indirect chelator—antibody method. Various antibodies are labelled by the latter, where the bifunctional chelating agent is initially conjugated to a macromolecule, which is then allowed to react with a metal ion, to form a metal-chelate-macromolecule complex. Due to the presence of the chelating agent, the biological properties of the labeled protein may be altered and must be assessed before clinical use. 

Figure 6. Chlorophyll a fluorescence profile obtained along Flight Line 7 of Figure 4 (top). Tne positions labeled a and K"show where the spectra of Figure 5a and 5b were obtained. Phycoerythrin fluorescence (middle) and temperature (bottom) profiles obtained along Flight Line 7 of Figure 4. The temperature profile was obtained with a PRT-5 radiometer.

BEHE, M., BECKER, W., GOTTHARDT, M., ANGERSTEIN, C.. BEHR, T.M., Improved kinetic stability of DTPA-DGlu as compared with conventional monofunctional DTPA in chelating indium and yttrium Preclinical and initial clinical evaluation of radiometal labelled minigastrin derivatives, Eur. J. Nucl. Med. Mol. Imaging 30 (2003) 1140-1146. 

Fig. 2. (A) Left lateral gamma images of dogs with acute experimental MI. Images a, c, e, and g were obtained after iv administration of conventionally modified " In-DTPA-antimyosin Fab (AM-Fab) images b, d, f, and h were obtained after administration of AM-Fab modified with 11 In-loaded chelating polymer (PL-AM Fab). The heavy load of chelating polymer-modified AM Fab with reporter radiometal permits one to obtain a clear infarct image in the left lateral oblique position only in 3 h (bright spot on image h). Whereas the use of traditionally labeled antibody requires <24 h to yield images of a comparable quality. From ref. 21.

The labeling of biomolecules with longer-lived radiometals is preferably performed with BFCs based on a macrocyclic core. If peptides are used as vector molecules, the slow kinetic of... 

A common drawback with macrocyclic ligands is their slow complexation rate (Jang et al. 1999). A way to overcome this problem is to increase the ring size. Following this idea, two larger chelators have been developed, one based on a pentaaza macrocycle (PEPA) and the other on a hexaaza macrocycle (HEHA) O Fig. 45.3). Both these chelators show much faster labeling kinetics with some radiometals (by a factor of about 100 times faster). Still, they have slower labeling kinetics than the acyclic chelator DTPA (by a factor of about 10) (O Table 45.4). 

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