Labeling of proteins, peptides, and estrogens with cyclopentadienyltricarbonylrhenium and technetium

A double ligand transfer reaction is described for the preparation of substituted cyclopentadienyltricarbonylrhenium or technetium complexes. In the reaction, perrhenate(VII) or pertechnetate(VII), respectively, is reduced and carbonylated by treatment with chromium trichloride and chromium hexacarbonyl, to provide a proposed alkoxy carbon Re(I) or Tc(I) intermediate. This intermediate undergoes a Cp ligand transfer reaction with an acyl-substituted ferrocene to provide the corresponding (acyl-cyclopentadienyl)tricarbonylrhenium or technetium complex. A coordinating solvent such as methanol is necessary to promote the reduction of perrhenate or pertechnetate, and a carbonyl substituent adjacent to the Cp ring is necessary to activate it for transfer from iron to rhenium or technetium.; Radioisotopes of technetium or rhenium (e.g., Tc-99m, Re-186 or Re-188) can be used in the double ligand transfer reaction to prepare organometallic radiopharmaceuticals. This potential is demonstrated by labeling the lysine residues of the model protein bovine serum albumin with Tc-99g- ((methoxycarbonyl)cyclopentadienyl) tricarbonyltechnetium. Moreover, the model peptides leucine enkephalin, substance P, and oxytocin are labeled with ((methoxycarbonyl)cyclopentadienyl) tricarbonylrhenium, and the somatostatin receptor imaging candidate octreotide, a cyclic octapeptide, is labeled using Tc-99m- ((methoxycarbonyl)cyclopentadienyl) tricarbonyltechnetium. The labeling sequences are performed by saponifying the respective technetium or rhenium methyl esters, and then activating the resulting carboxylic acids using N-hydroxysuccinimide, 1-hydroxybenzotriazole or 1-hydroxy-7-azabenzotriazole. The coupling reactions between the active esters and the protein or peptides typically proceed in yields exceeding 70%. The Tc-99m-octreotide conjugate showed receptor-mediated uptake in the pancreas and adrenals of female Sprague-Dawley rats, which was blocked (80% and 93%, respectively) by excess unlabeled octreotide.; The conjugation of cyclopentadienyltricarbonylrhenium to molecules having an affinity for the estrogen receptor is described. A variety of derivatives were prepared using either an indirect labeling or a preformed chelate approach, and of the compounds synthesized, ((17{dollar}beta{dollar}-estradiol-17{dollar}alpha{dollar}-yl)-ethynylcyclopentadienyl) tricarbonylrhenium and its 11{dollar}beta{dollar}-chloromethyl, ethyl and methoxy derivatives are attractive candidates for imaging estrogen receptors in vivo, having relative binding affinities (RBA's) for the estrogen receptor of 7.29%, 283%, 283% and 52.6%, respectively.