Development and evaluation of a novel radioiodinated vesamicol analog as a sigma receptor imaging agent

Abstract

BackgroundSigma receptors are highly expressed in human tumors and should be appropriate targets for developing tumor imaging agents. Previously, we synthesized a vesamicol analog, (+)-2-[4-(4-iodophenyl)piperidino]cyclohexanol ((+)-pIV), with a high affinity for sigma receptors and prepared radioiodinated (+)-pIV. As a result, (+)-[125I]pIV showed high tumor uptake in biodistribution experiments. However, the accumulation of radioactivity in normal tissues, such as the liver, was high. We supposed that some parts of the accumulation of (+)-pIV in the liver should be because of its high lipophilicity, and prepared and evaluated a more hydrophilic radiolabeled vesamicol analog, (+)-4-[1-(2-hydroxycyclohexyl)piperidine-4-yl]-2-iodophenol ((+)-IV-OH).Methods(+)-[125I]IV-OH was prepared by the chloramine T method from the precursor. The partition coefficient of (+)-[125I]IV-OH was measured. Biodistribution experiments were performed by intravenous administration of a mixed solution of (+)-[125I]IV-OH and (+)-[131I]pIV into DU-145 tumor-bearing mice. Blocking studies were performed by intravenous injection of (+)-[125I]IV-OH mixed with an excess amount of ligand into DU-145 tumor-bearing mice.ResultsThe hydrophilicity of (+)-[125I]IV-OH was much higher than that of (+)-[125I]pIV. In biodistribution experiments, (+)-[125I]IV-OH and (+)-[131I]pIV showed high uptake in tumor tissues at 10-min post-injection. Although (+)-[131I]pIV tended to be retained in most tissues, (+)-[125I]IV-OH was cleared from most tissues. In the liver, the radioactivity level of (+)-[125I]IV-OH was significantly lower at all time points compared to those of (+)-[131I]pIV. In the blocking studies, co-injection of an excess amount of sigma ligands resulted in significant decreases of tumor/blood uptake ratios after injection of (+)-[125I]IV-OH.ConclusionsThe results indicate that radioiodinated (+)-IV-OH holds a potential as a sigma receptor imaging agent.

Comparison of Radioiodine- or Radiobromine-Labeled RGD Peptides between Direct and Indirect Labeling Methods

“…The reaction mixture was rotated for 1 h, and 1 mL of methanol was added to react for another 30 min. Next, the peptide chain was constructed in cycles of (I) 15 To cleave peptides from the resin, the resin-bound peptides were treated with 30% HFIP in dichloromethane for 5 min. After filtration, the solvent in the filtrate was removed in vacuo.…”

“…[2-[2-(tert-Butyloxycarbonyl) aminoethoxy] ethoxy] acetic acid (Boc-NH-EG 2 -COOH) (14) was prepared in 4 steps (5%) from 2-[2-(2-chloroethoxy) ethoxy] ethanol using a method described previously. (13), which was synthesized using a method described previously, 24) was dissolved in 100 µL of DMF.…”

“…[8][9][10][11][12][13] Among the halogens, many useful radioisotopes for nuclear medicine and life sciences exist, such as 18 F (for PET), 76 Br (for PET), 77 Br (for basic research or Auger therapy), At (for α therapy). 14) A labeling method for proteins that uses radioiodine and an oxidation agent, such as chloramine-T, has been used classically. The chloramine-T method can effectively and easily introduce radioiodine into tyrosine residue in proteins.…”

“…Moreover, the chloramine-T method can be adapted for peptides with a tyrosine residue and small molecules containing a phenolic group. 15,16) Another representative labeling approach that uses radioiodine is a method using an iododestannylation reaction from a corresponding precursor with a trialkylstannyl group. This method has been widely used for radioiodination of small molecules 17) or indirect labeling.…”

Inhibition of Cholinergic Signaling Causes Apoptosis in Human Bronchioalveolar Carcinoma

“…Ogawa and colleagues evaluated radioiodinated vesamicol analogs for tumor imaging and antitumor activity (42,43). They found that radioiodinated vesamicol analogues suppressed the growth of human prostate cancer cells in mice model.…”