title: Preparation of cyclotron-produced 186Re and comparison with reactor-produced 186Re and generator-produced 188Re for the labeling of bombesin.
abstract: The radioisotopes (186)Re and (188)Re have been extensively investigated for various forms of radiotherapy due to their useful and high-abundance beta particle emissions, low-abundance and imageable gamma-rays, and chemical resemblance to technetium. In addition, (188)Re is available in no-carrier-added (NCA) form from long lived W-188 generators, whereas (186)Re can be produced in large quantities from reactors, although not in NCA form. However, NCA (186)Re can be produced on a cyclotron by a (p,n) reaction on (186)W. The purpose of this study was to compare labeling of the peptide bombesin with these three forms of rhenium radioisotopes. Cyclotron-produced NCA (186)Re was separated radiochemically from enriched (186)W (96.9%) targets using high-purity methyl ethyl ketone (MEK). The resulting (186)Re-MEK was then loaded onto a small alumina column to separate the resulting NCA (186)Re from any remaining (186)W. The experimental levels of impurities associated with (186)Re at the end of the separation process were found to be 5.7 x 10(-6) Ci of (182)Re (0.57%, t(1/2) = 12.7 h) and 1.283 x 10(-5) Ci of (182m)Re (1.28%, t(1/2) = 2.67 days). The radionuclidic purity of the separated (186)Re was found to be 99.6%, whereas the chemical identity was determined by reversed phase high-performance liquid chromatography (RP-HPLC) to be perrhenate ((186)ReO(4)(-)). Generator-produced (188)ReO(4)(-) from a (188)W/(188)Re generator (Oak Ridge National Laboratory) and CA (186)ReO(4)(-) produced from a (185)Re(n,gamma)(186)Re reaction at the University of Missouri Research Reactor (MURR) were used for comparison with the NCA (186)Re in subsequent studies. N(3)S-5-Ava-BBN(7-14)NH(2) conjugates provide flexibility for designing (186,188)Re-labeled conjugates that retain high in vitro and in vivo specificity targeting of GRP receptor-expressing cells. This study showed that the N(3)S-5-Ava-BBN(7-14)NH(2) could be labeled with (186,188)Re following the preconjugation, postmetallation approach. The (186,188)Re(V)O-N(3)S-5-Ava-BBN(7-14)NH(2) complexes were found to form stable complexes following the reduction of perrhenate (Re(VII)O(4)(-)) with stannous chloride at room temperature, as verified by HPLC and stability studies. The radiolabeling yield was found to be >90%. The HPLC chromatograms of (186,188)Re-N(3)S-5-Ava-BBN(7-14)NH(2) complexes revealed two peaks for each conjugate, reflecting the presence of syn- and anti-isomers, which were resolvable by HPLC but re-isomerized on separation. The biodistribution studies showed that the compounds were excreted through the renal and hepatobiliary systems and demonstrated receptor-specific uptake with an average pancreas accumulation of 8.15% ID/g at 1 h postinjection. Administration of cold BBN effectively blocked pancreatic uptake and further reflects the high specificity this conjugate has for the GRP receptors. At low levels of radioactivity, radiolysis effects were not observed. Scale-up may or may not elicit this effect, particularly for the higher energy beta emitter (188)Re. The biodistribution studies demonstrated that the CA and NCA (186,188)Re conjugates behaved similarly, raising the question of whether NCA (186,188)Re is necessary for specific tumor receptor targeting.
authors.affiliation: Department of Chemistry, University of Missouri-Columbia, 65211, USA.
authors.forename: Moustapha E
authors.initials: ME
authors.lastname: Moustapha
authors.forename: Gary J
authors.initials: GJ
authors.lastname: Ehrhardt
authors.forename: Charles J
authors.initials: CJ
authors.lastname: Smith
authors.forename: Lawrence P
authors.initials: LP
authors.lastname: Szajek
authors.forename: William C
authors.initials: WC
authors.lastname: Eckelman
authors.forename: Silvia S
authors.initials: SS
authors.lastname: Jurisson
mesh_terms: D000818:Animals; D001839:Bombesin / Q000737:chemistry* / Q000493:pharmacokinetics* / Q000627:therapeutic use; D017357:Cyclotrons; D005260:Female; D007553:Isotope Labeling / Q000379:methods*; D008657:Metabolic Clearance Rate; D051379:Mice; D009688:Nuclear Reactors; D009928:Organ Specificity; D011868:Radioisotopes / Q000737:chemistry* / Q000493:pharmacokinetics* / Q000627:therapeutic use; D019275:Radiopharmaceuticals / Q000138:chemical synthesis / Q000493:pharmacokinetics / Q000627:therapeutic use; D012211:Rhenium / Q000737:chemistry* / Q000493:pharmacokinetics* / Q000627:therapeutic use; D014018:Tissue Distribution
chemical_list: D011868:Radioisotopes; D019275:Radiopharmaceuticals; D012211:Rhenium; D001839:Bombesin