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A one-day satellite workshop was organized to coincide with the 17th International Symposium on Radiopharmaceutical Sciences held in Aachen, Germany, April 30-May 4, 2007. The workshop, “Production and application of ‘non-standard’ PET nuclides”, was held on Sunday April 29, 2007 at the Eurogress Aachen and was organized by J. Lewis, PhD, L. Tang, and M. Welch, PhD. The workshop was designed for the radiopharmaceutical community discussing the production, use and dissemination of the “non-standard” PET nuclides. The definition of “nonstandard” positron emission tomography (PET) nuclides included 45Ti, 60Cu, 61Cu, 64Cu, 66Ga, 72As, 74As, 76Br, 86Y, 89Zr, 94mTc and 124I. The workshop was supported by the grant Research Resource for Cancer Applications (R24 CA86307) funded by the National Cancer Institute at the National Institutes of Health. The workshop was attended by over 110 scientists and engineers from over 20 countries from all over the world and was designed with an open forum style to allow for discussions and interactions by all participants. All of the invited speakers were asked to make a contribution to this edition of the Quarterly Journal of Nuclear Medicine. The individual articles following this introduction are reviews of their area of expertise and the current state-of-the-art. This introduction briefly describes the role of the workshop, the aims and the general outcome. Also, the translation of these nuclides to the clinic, perhaps the most important goal of this work is discussed in this introductory article.

Sigma receptors are membrane-bound proteins having high affinities for a variety psychotropic drugs with opiate-type structures. The sigma receptor subtypes, sigma-1 and sigma-2, have different molecular weights and pharmacological roles.1 Many cancer cell lines (breast, melanoma, prostate cancer) express high levels of sigma receptors,2,3 and proliferative tumor cells express much higher levels of sigma-2 receptors than quiescent cells.4,5 Thus, the sigma-2 receptor has been proposed as a suitable target for imaging proliferative tumor cells. While many ligands are selective for the sigma-1 receptor or are nonselective, very few ligands are selective for the sigma-2 receptor. A radiopharmaceutical based on an azabicyclo[3.3.1]nonane framework was developed by Mach,6 who demonstrated that the rhenium surrogate showed exceptional sigma-2 selectivity; later this agent was labeled with technetium-99m by Kung for tissue distribution studies.7 In considering potential fluorine-18 labeled sigma-2 receptor ligands, our attention focused on members of an indole piperidine series, especially 1 (LU 28-179), which is reported to have a remarkably high sigma-2 binding affinity and selectivity.8,9 Figure 1. The structure of indole piperidine ligands and their inhibition constants toward sigma receptors. Target compounds 1 and 2 were prepared in several steps by a route based on a previously described method,7 with modifications making it more efficient for the synthesis of the precursor molecule (3); compounds 1 and 2 showed high binding affinity and good selectivity (6 fold) for the sigma-2 receptor (Figure 1). The preparation of [18F]-labeled indole piperidine [18F]1 was achieved in two steps from a o-nitroaldehyde precursor (3). Aromatic [18F]fluorination was not reproducible when 3 was treated with F-18 fluoride in the presence of Bu4NOH under microwave heating conditions. However, by using F-18, K2CO3 and kryptofix[2.2.2] under microwave heating, we obtained radiochemical yields of 5-50%. The final decarbonylation step with Wilkinson’s catalyst was studied in various solvents. Decarbonylation using dioxane as solvent produced [18F]1, but with toluene, extensive decomposition resulted. Herein, we present the synthesis of precursor 3, optimization of [18F]fluorination, and decarbonylation to produce [18F]Lu 28-179 (Scheme 1). Future work to prepare [18F]1 will be done using an alternate synthetic route.10 Supported by DOE grants 86ER60401 (to JAK) and 84ER60218 (to MJW). Ref) 1. Vilner, B. J. et al. Cancer Res. 55: 408-413 (1995) 2. John, C. S. et al. Cancer Res. 59: 4578-4583 (1999) 3. Quirion, R. et al. Trends Phrmacol. Sci. 13: 85-6 (1992) 4. Mach, R. H. et al. Cancer Res. 57: 156-161 (1997) 5. Wheeler, K. T. et al. Br. J. Cancer 82: 1223-1232 (2000) 6. Mach et al., J. Labelled Cmpds Radiopharm 2001; 44: 899-908 7. Choi, S.-R. Nucle. Med. Biol. 28: 657-666 (2001) 8. Perregaard, J. J. Med. Chem. 38: 1998-2008 (1995) 9. Moltzen, E. K. J. Med. Chem. 38: 2009-2017 (1995) 10. Wüst, F. et al. J. Label. Compd. Radiopharm. 48: 31-43 (2005)

The diagnosis and staging of breast cancer could be improved by the development of radiopharmaceutical imaging agents that provide a noninvasive determination of the estrogen receptor (ER) status of tumor cells. Agents labeled with 99mTc would be especially valuable in this regards. In attempting to achieve this goal, we synthesized four 99mTc-labeled 7alpha-substituted estradiol complexes. One complex utilizes the "3+1" mixed ligand design to introduce the Tc metal, whereas the other three took advantage of the cyclopentadienyltricarbonylmetal (CpTM) design. The Tc moieties were attached to the 7alpha position of estradiol with a hexyl tether, a monoether tether, or a polyether tether. The corresponding rhenium compounds have binding affinities for the ER of 20-45% compared with estradiol. Radiochemical yields of the Tc-labeled compounds ranged from approximately 15% for the CpT-Tc complexes to 95% for the 3+1 inorganic complex. Tissue distribution studies in immature female rats showed low nonreceptor-mediated uptake in the target organs and high uptake in the nontarget organs such as liver and fat. These complexes represent the first time that estradiol has been labeled at the 7alpha position with 99mTc and provide a further refinement of our understanding of ligand structure-binding affinity correlations for the ER

The diagnosis and staging of breast cancer could be improved by the development of imaging radiopharmaceuticals that provide a non-invasive determination of the estrogen receptor (ER) status of tumor cells. Towards this goal, we have synthesized a number of Re and Tc-labeled estradiol (1) mimics based on the conjugated design, which tethers a metal-containing moiety to an existing steroid. In this study, the 7alpha position of estradiol was chosen as the tether site, due to its well known tolerance of bulky substituents. 1 The metal was stabilized using either the "3+1" design (2,3), or the cyclopentadienyltricarbonylmetal (CpTM) approach (4,5,6) . In the "3+1" design, a tridentate ligand and a monodentate ligand surround an oxometal core.2 In the CpTM design, a substituted Cp and three carbonyls are coordinated to a Re/Tc(I) center.3,4 The advantages of using the "3+1" and CpTM desings are the well-established stability of both systems, as well as the ability to produce both systems efficiently at the tracer level.2,4 The first tether used was a hexyl spacer, and the synthesis of the precursors for targets 2-6 started with THP-protected estradiol 7 (Scheme 1). After oxidation to ketone 8 using a previously published method, standard alkylation conditions introduced the hexene side chain to form 9 , with BEt3 as an additive to stabilize the enolate and prevent O-alkylation.

Heparin, a polyanionic glycosaminoglycan, is used routinely prior to the induction of cardiopulmonary bypass. Earlier observations in our laboratory suggested that the postoperative bleeding which occurs, despite neutralization of heparin with protamine, is secondary to hypothermia and dilutional anemia during bypass. An additional, potential mechanism for excessive bleeding following cardiopulmonary bypass is that heparin activates the fibrinolytic system, which may, in turn, adversely affect hemostasis. To understand better the effects of heparin administration on the fibrinolytic system in vivo, we simulated the anticoagulant regimen of cardiopulmonary bypass by administering increasing doses of intravenous heparin to five adult baboons over 60 minutes. We measured fibrinolytic parameters serially following heparinization, and demonstrated that heparin induces activation of the fibrinolytic system. We showed that the fibrinolytic system was activated in vivo as evidenced by an increase in plasmin activity and immunoreactive plasmin light chain, as well as an increase in immunoreactive fibrinogen fragment E in vitro. These results demonstrate that the fibrinolytic system is activated in vivo by the administration of heparin during cardiopulmonary bypass. These data suggest that, despite administration of a neutralizing agent such as protamine, heparin may contribute to postoperative bleeding complications following cardiopulmonary bypass surgery owing principally to its longer-lived effects on the fibrinolytic system.