Preparation of cyclotron-produced 186Re and comparison with reactor-produced 186Re and generator-produced 188Re for the labeling of bombesin

The radioisotopes 186Re and 188Re have been extensively investigated for various forms of radiotherapy due to their useful and high-abundance β particle emissions, low-abundance and imageable γ-rays, and chemical resemblance to technetium. In addition, 188Re is available in no-carrier-added (NCA) form from long lived W-188 generators, whereas 186Re can be produced in large quantities from reactors, although not in NCA form. However, NCA 186Re can be produced on a cyclotron by a (p,n) reaction on 186W. The purpose of this study was to compare labeling of the peptide bombesin with these three forms of rhenium radioisotopes. Cyclotron-produced NCA 186Re was separated radiochemically from enriched 186W (96.9%) targets using high-purity methyl ethyl ketone (MEK). The resulting 186Re-MEK was then loaded onto a small alumina column to separate the resulting NCA 186Re from any remaining 186W. The experimental levels of impurities associated with 186Re at the end of the separation process were found to be 5.7x10-6 Ci of 182Re (0.57%, t 1/2=12.7 h) and 1.283x10-5 Ci of 182mRe (1.28%, t 1/2=2.67 days). The radionuclidic purity of the separated 186Re was found to be 99.6%, whereas the chemical identity was determined by reversed phase high-performance liquid chromatography (RP-HPLC) to be perrhenate (186ReO4-). Generator-produced 188ReO4- from a 188W/188Re generator (Oak Ridge National Laboratory) and CA 186ReO4- produced from a 185Re(n,γ)186Re reaction at the University of Missouri Research Reactor (MURR) were used for comparison with the NCA 186Re in subsequent studies. N3S-5-Ava-BBN(7-14)NH2 conjugates provide flexibility for designing 186,188Re-labeled conjugates that retain high in vitro and in vivo specificity targeting of GRP receptor-expressing cells. This study showed that the N3S-5-Ava-BBN(7-14)NH2 could be labeled with 186,188Re following the preconjugation, postmetallation approach. The 186,188ReVO-N3S-5-Ava-BBN(7-14)NH2 complexes were found to form stable complexes following the reduction of perrhenate (ReVIIO4-) 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 186,188Re-N3S-5-Ava-BBN(7-14)NH2 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 β emitter 188Re. The biodistribution studies demonstrated that the CA and NCA 186,188Re conjugates behaved similarly, raising the question of whether NCA 186,188Re is necessary for specific tumor receptor targeting