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

Moustapha, Moustapha E.; Ehrhardt, Gary J.; Smith, Charles J.; Szajek, Lawrence P.; Eckelman, William C.; Jurisson, Silvia S.

doi:10.1016/j.nucmedbio.2005.09.006

« Previous Next »Nuclear Medicine and Biology
Volume 33, Issue 1 , Pages 81-89, January 2006

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

Moustapha E. Moustapha
- Department of Chemistry, University of Missouri-Columbia, Columbia, MO 65211, USA
- University of Missouri Research Reactor (MURR), University of Missouri-Columbia, Columbia, MO 65211, USA
Gary J. Ehrhardt
- Department of Chemistry, University of Missouri-Columbia, Columbia, MO 65211, USA
- University of Missouri Research Reactor (MURR), University of Missouri-Columbia, Columbia, MO 65211, USA
Charles J. Smith
- Department of Radiology, University of Missouri-Columbia, Columbia, MO 65211, USA
- University of Missouri Research Reactor (MURR), University of Missouri-Columbia, Columbia, MO 65211, USA
- Research Services, Harry S. Truman Memorial Veterans' Hospital, Columbia, MO 65201, USA
Lawrence P. Szajek
- Positron Emission Tomography Department, National Institutes of Health, Bethesda, MD 20892-1180, USA
William C. Eckelman
- Positron Emission Tomography Department, National Institutes of Health, Bethesda, MD 20892-1180, USA
Silvia S. Jurisson
- Department of Chemistry, University of Missouri-Columbia, Columbia, MO 65211, USA
- Corresponding author. Tel.: +1 573 882 2107.

Received 24 August 2005; received in revised form 28 September 2005; accepted 29 September 2005.

Abstract

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 5.7×10⁻⁶ Ci of ¹⁸²Re (0.57%, t_1/2=12.7 h) and 1.283×10⁻⁵ 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 ^186,188Re^VO-N₃S-5-Ava-BBN(7–14)NH₂ complexes were found to form stable complexes following the reduction of perrhenate (Re^VIIO₄⁻) 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.