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    20061026Bressanone64EC92.doc 20061026Bressanone64EC92.doc Document Transcript

    • Professor Ulderico Mazzi, the Chairman of the Seventh International Symposium on Technetium in Chemistry and Nuclear Medicine stated in the preface to the Meeting Proceedings that “the need of tracers other than “essential” radiopharmaceuticals able to reach newly discovered molecular targets puts technetium in competition with other metal or non-metal radionuclides” [1]. Thus, the expansion of this meeting to discuss other radiometals is most appropriate because comparisons are the natural outcome of this competition. This competition also serves to focus Tc chemistry and Tc radiopharmaceuticals on its strengths. Given that only a handful of small molecules ( < 500 Da) radiolabeled with metals have demonstrated targeted binding in vivo because of the large structural perturbation, radiolabeling with radiometals have been used predominately to trace higher molecular weight molecules such as peptide, proteins, and nanoparticles. For example, as presented at this meeting, small (<500 Da) targeted molecules radiolabeled with Technetium-99m that have been validated in vivo are few, for example, TRODAT-1 [2], a radiolabeled dipeptide based on the ACE inhibitor lisinopril [3], a radiolabeled analog of estradiol [4], and an analog of naltrindole [5]. New Chelating Agents and New Targets In this 7th meeting, there was still a major emphasis of “new” chelating agents for Tc (>40 manuscripts) presumably with the general goal of reducing the molecular weight, the molecular size, the charge distribution, and the number of hydrogen donors and acceptors, although the goal was not always articulated as such. There were also new Tc-containing radiotracers with the potential to target the formyl peptide receptor on leukocytes, hypoxia (MISO analogs), DNA (thymidine analogs), cationic uptake in the myocardium, DNA via zinc fingers, amino acid transporters such as LAT-1, the estrogen receptor (estradiol analogs), infection (fluoroquinoline and ciprofloxacin), the 5-HT1A receptor, Alzheimer’s plaque, fatty acid metabolism, renal secretion, thymidine kinase, the insulin receptor, and the epidermal growth factor receptor. At the time of the meeting, only a few of these had been validated as tracers of some aspect of the targeted biochemical pathway. Technetium-99m labeled peptides were reviewed by Garcia-Garayo and Schubiger [6]. The validated Tc radiolabeled peptides at this time are various analogs of bombesin, VIP, MSH, NT, and somatostatin. Peptides for thrombosis imaging and infection/inflammation imaging, heart disease, and angiogenesis were also characterized. Challenges for Technetium-99m Radiopharmaceuticals This symposium is proof that there are many targeted radiotracers labeled with Technetium-99m. Validated Technetium-99m radiopharmaceuticals are clearly available; why are there not more Technetium-99m radiopharmaceuticals in the clinic? The probable factors are three: the cost of bringing a radiotracer to the market place given the government regulations for approval, the lack of high resolution and high sensitivity SPECT cameras, and the lack of a clear definition of the impact of the new radiotracer on clinical outcome. These challenges were addressed in the last session of the meeting entitled “The Search for New Targets for Clinical Imaging” [7,8,9,10.11]. Many radiotracers have had a major impact on understanding the role of biochemical pathways in vivo, especially in the neurosciences. 1
    • However, fewer have been advanced to the clinic as approved drugs and fewer yet have had an impact on patient outcome in spite of the many therapeutic drugs being developed for neurological and psychiatric diseases. Defining the Biological Space for Technetium-99m Radiopharmaceuticals The development of “Essential” Tc radiopharmaceuticals, beginning with 99mTc DTPA and culminating with the myocardial perfusion agents has declined recently due to the advances of other imaging modalities that monitor high capacity biochemical systems in vivo and the difficulty of incorporating Tc into structurally complicated small (<500 Da) biomolecules. This has clearly become the domain of F-18 and C-11. The difficulty of “essential” radiotracers in the competitive field of external imaging, the emphasis on the sensitivity of radiotracers to monitor relatively low capacity targets such as receptors, transporters, and enzymes, and the advances made in PET, especially in low molecular weight biochemicals, has led to a decline in the application of Technetium-99m chemistry and radiopharmaceuticals to clinical medicine. Given the ideal imaging properties of Technetium-99m, the favorable absorbed radiation dose per imaged photon, and the wealth of chemistry, it was disappointing to see a large number of targeted compounds labeled with other metallic radionuclides without a comparison to the Tc analog. The lack of comparison can be explained in part by the difference in imaging resolution and sensitivity between SPECT and PET, giving PET a clear edge. Radionuclides emitting a positron (e.g., Cu-64 and Ga-68) have a current advantage over single photon emitting radionuclides in the resolution of the human imagers, but in the small animal imaging field SPECT is becoming increasingly competitive with PET by exhibiting higher resolution and increasingly comparable sensitivity [12]. In addition, the ability to monitor two emission energies and therefore two radiopharmaceuticals simultaneously gives SPECT another advantage. It appears that SPECT for human studies will be following this trend in instrumentation as well and thus Technetium-99m should be competitive in all situations as long as the biological half life of the targeted molecule is consistent with the physical half life of Technetium-99m. The current paradigm of having all Technetium-99m radiopharmaceuticals available as instant kits was put forth by Professor John Valliant as another possible explanation for the slow introduction of Technetium-99m radiopharmaceuticals into the clinic [13]. The emphasis on Instant Kits for Technetium-99m & Re radiolabeling has delayed the introduction of new targeted molecules even though the trend is toward distributing radiopharmaceuticals from a central radiopharmacy. For example, if F-18 radiotracers had to be formulated as a one or two step kit rather than being distributed via a radiopharmacy after a relatively complicated synthesis, it is unlikely that F-18 radiotracers would be readily available today. In the same vein, another reason that metallic radionuclides other than Tc are chosen more frequently is the commercial supply of bifunctional chelating agents of either the acyclic or cyclic variety used for In-111, Cu-64, Ga-68, and the lanthanides. Technetium has not enjoyed the same advantage except for the 99mTc tricarbonyl kit distributed by Mallinckrodt, 2
    • Inc [14]. Once again, central radiopharmacy preparation of the Technetium-99m radiopharmaceutical may eliminate that advantage. The Panel Recommendations Given that the solution to the technical difficulties to again make Technetium-99m the dominant radionuclide are in sight, the choice of the target must be made with care to maximize the efforts of the relatively few radiopharmaceutical scientists. The Panel of Drs. Eckelman, Erba, Schwaiger, Wagner, and Alberto discussed the goals of developing radiopharmaceuticals for general disease control points such as proliferation, hypoxia, apoptosis, angiogenesis, inflammation, and metastasis. The panel also discussed another approach, namely to monitor the same control point that the pharmaceutical companies are targeting using external imaging. A single disease-control- point must be identified as the drug target; likewise a single control point will then be available for the imaging agent. This reduces drug targeting of an organism to drug targeting a single protein expression product. This is clearly a reductionist approach to drug discovery, driven by the explosion in identification of new targets in the post-genomic era. However, since most imaging procedures are limited to a single or two scans per patient per session, it is ideal as an imaging approach. These two approaches are analogous to the pharmaceutical approach of developing a blockbuster that is therapeutically effective in a wide range of cancers as opposed to developing a targeted molecule that is effective in a small population of cancers. The latter approach is the so-called individualized or personalized medicine that is the hope of higher therapeutic efficiency. What about the large number of targeted radiotracers developed to date that has yielded interesting biochemical data on various diseases? Why have they not had more of a clinical impact? The answer may be in dissecting the two approaches presented by the panel. The former approach for general disease control points is well under way although the first phase of radiopharmaceuticals needs further validation and refinement and few have been radiolabeled with Technetium-99m for comparison. It is important that the research efforts demonstrate that radiotracers labeled with either a metallic radionuclide or a radiohalogen undergo a thorough validation to demonstrate what biochemistry is accurately traced by the analog. Krohn et al. define this as an ongoing process given that using an analog as a tracer for a specific biochemical such as glucose or thymidine is susceptible to non parallel changes in biochemical parameters of the analog compared to the parent compound in terms of flow, permeability, metabolism, flux, receptor density and its associated binding rate constant [15]. This has not been investigated uniformly for the radiotracers designed to monitor the general control point and is seldom addressed for radiometallic tracers. A key factor that applies to both classes of new targets is the cost and time to obtain approval for new radiopharmaceuticals. The exploratory IND in the USA has decreased the amount of material needed to complete the preliminary toxicology-pathology study, but has not decreased the time for the complete study or the cost of the pathologist’s examination of the 3
    • tissue. Safety is a primary concern of all investigators, but the high specific activities of the radiotracers developed today combined with an understanding of the pharmacologic effect of the parent compound should lead to a faster approval process for first in man studies if not for full clinical approval. The second approach to radiolabeling a key protein expression product affected by the experimental therapeutic drug requires close collaboration with either a university pharmacologist or a pharmaceutical company. Producing a radiolabeled analog of the drug with the proper validation studies will lead to an important preclinical parameter, namely drug occupancy and the concomitant parameter of the duration of drug occupancy. However, radiolabeling an analog of the drug itself will not lead to an understanding of the effectiveness of the drug because it will be a two variable experiment that will make it difficult to interpret the changes in radioactivity at the target protein site. Unless drug washout is assured, something that is not likely to be possible during chemotherapy, changes in the radioactivity at the target could be caused by changes in the number of binding sites or changes in the drug occupancy of the target. A clearer interpretation of the imaging results is achieved if the change in the ultimate expression product is monitored by external imaging. One example of the latter approach of targeting a single control point in a particular disease is the external imaging of HER2 expression as a function of treatment using an inhibitor of heat shock protein 90 (HSP-90). 17-allylaminogeldanamycin (17-AAG) is the first Hsp90 inhibitor to be tested in a clinical trial. This drug induces proteasomal degradation of HER2 by binding to Hsp90 chaperone protein. The challenge is to monitor this treatment using external imaging. The lead for targeting the HER2 protein comes from the clinical trials of an antibody to HER2. Trastuzumab is such an antibody for HER2 (also known as ErbB2 & Neu), which is a cell surface glycoprotein with tyrosine kinase activity. Based on the clinical trials, HER2 over-expression is now an entry criteria and amplification/over-expression is predictive for response in breast cancer. The group at Sloan Kettering Memorial Cancer Center under the leadership of Dr. Steven Larson has developed an antibody fragment for HER2 radiolabeled with Ga-68 whose physical half life matches the biological half life of the antibody fragment. The Ga-68 radiolabeled F(ab’)2 monitors the change in the protein expression product as a function of treatment with 17-AAG. The effectiveness of 17-AAG was demonstrated using small animal imaging in BT-474 tumor bearing mice. This approach does not monitor the effectiveness of 17-AAG binding to HSP 90 directly, but rather to the protein expression product and therefore does not suffer from the critique that the observation could result from either occupancy or reduced number of HER2. Only the latter is measured with this approach [16]. The consensus of the meeting was the bright future for Technetium-99m if the resolution of SPECT is improved and the regulatory pathway is in concert with the low mass injections. But more importantly, radiopharmaceutical scientists, especially mentors of pre- and post- graduate trainees, need to analyze their choice of targets with the view of having an impact on clinical outcome. The Proceedings of the Seventh International Symposium on Technetium in Chemistry and Nuclear Medicine held in Bressanone, Italy on Sept 6-9, 2006 and the proceedings of the 4
    • previous six meetings are available from Servizi Grafici Editorali snc at sge@sgeditoriali.it. The next meeting will be held in 2010 at the same location under the name of the International Symposium on Technetium and Other Metals in Chemistry, Biology and Nuclear Medicine to reflect changes in the goals of the meeting. William C Eckelman1, Paola A Erba2, Markus Schwaiger3, Henry N Wagner, Jr4, Roger Alberto5, Ulderico Mazzi6. 1. Molecular Tracer LLC, Bethesda MD 20814. 2. Regional Center of Nuclear Medicine, University of Pisa Medical School, Via Roma 67 Pisa, I-56126 3. Nuk. Med. Klinik -U Poliklinik Klinik, TU Muen./Ismanger Str. 22, Muenchen, D-81675, Germany 4. John Hopkins Bloomberg School of Public Health, 5607 Wildwood Lane, Baltimore MD 21209 5. Institute of Inorganic Chemistry, University of Zurich, Winterthurerstr. 190, CH-8057 Zurich Switzerland. 6. Dept. of Pharmaceutical Sciences, University of Padua, via Marzolo 5, 35132 Padova Italy. 5
    • REFERENCES [1] Mazzi U. Preface. In: Mazzi U, Editor. Proceedings of the Seventh International Symposium on Technetium in Chemistry and Nuclear Medicine. Padova Italy: Servizi Grafici Editoriali snc,; 2006, p. XXV. [2] Kung JF, Kung M-P, Plossl K, Choi SR. 99mTc labeled complexes as brain imaging agents. In: Mazzi U, Editor. Proceedings of the Seventh International Symposium on Technetium in Chemistry and Nuclear Medicine. Padova Italy: Servizi Grafici Editoriali snc,; 2006, p. 355-370. [3] Femia FJ, Maresca KP Joyal JL et al. Novel M(CO)3+ [M= Tc,Re] containing derivatives of lisinopril for imaging angiotensin converting enzyme (ACE). In: Mazzi U, Editor. Proceedings of the Seventh International Symposium on Technetium in Chemistry and Nuclear Medicine. Padova Italy: Servizi Grafici Editoriali snc,; 2006, p. 627-630. [4] Norenberg JP, Nayak TK, Anderson TL et al. Characterization of in vivo pharmacokinetics of estrogen receptors-targeted tridentate pyridin-2-yl hydrazine tricarbonyl-99M Tc estradiol chelate. In: Mazzi U, Editor. Proceedings of the Seventh International Symposium on Technetium in Chemistry and Nuclear Medicine. Padova Italy: Servizi Grafici Editoriali snc,; 2006, p. 459-464. [5] Lever JR, Duval RA, Allmon RL et al. Synthesis and pharmacological studies of an indium-labeled DOTA conjugate of naltrindole having high affinity for delta opioid receptors. In: Mazzi U, Editor. Proceedings of the Seventh International Symposium on Technetium in Chemistry and Nuclear Medicine. Padova Italy: Servizi Grafici Editoriali snc,; 2006, p. 207-210. [6] Garcia Garayoa E, Schubiger PA. Peptide-based radiopharmaceuticals radiolabelled with Tc-99m and Re-188 as potential diagnostic and therapeutic agents. In: Mazzi U, Editor. Proceedings of the Seventh International Symposium on Technetium in Chemistry and Nuclear Medicine. Padova Italy: Servizi Grafici Editoriali snc,; 2006, p. 247-262. [7] Eckelman WC. Finding the right targeted probe for the right target for the right disease. In: Mazzi U, Editor. Proceedings of the Seventh International Symposium on Technetium in Chemistry and Nuclear Medicine. Padova Italy: Servizi Grafici Editoriali snc,; 2006, p. 657-664. [8] Erba PA, Signore A, Mariani G. Prospective molecular targets for the development of 99m Tc-labeled agents with potential clinical use. In: Mazzi U, Editor. Proceedings of the Seventh International Symposium on Technetium in Chemistry and Nuclear Medicine. Padova Italy: Servizi Grafici Editoriali snc,; 2006, p. 665-681. [9] Wester H-J, Schottelius M, Schwaiger M. Search for new targets for clinical imaging: medical aspects. In: Mazzi U, Editor. Proceedings of the Seventh International Symposium on Technetium in Chemistry and Nuclear Medicine. Padova Italy: Servizi Grafici Editoriali snc,; 2006, p. 683-691. [10] Wagner, Jr. HN. Facilitating radiopharmaceutical approval. In: Mazzi U, Editor. Proceedings of the Seventh International Symposium on Technetium in Chemistry and Nuclear Medicine. Padova Italy: Servizi Grafici Editoriali snc,; 2006, p. 693-694. [11] Alberto R. Search of new targets for clinical imaging: chemistry aspects. In: Mazzi U, Editor. Proceedings of the Seventh International Symposium on Technetium in 6
    • Chemistry and Nuclear Medicine. Padova Italy: Servizi Grafici Editoriali snc,; 2006, p. 695-698. [12] Levin CS. Primer on molecular imaging technology. Eur J Nucl Med Mol Imaging. 2005;32 Suppl 2:S325-45. [13] Valliant J. Roundtable Discussion. In: Mazzi U, Editor. Proceedings of the Seventh International Symposium on Technetium in Chemistry and Nuclear Medicine. Padova Italy: Servizi Grafici Editoriali snc,; 2006. [14] Isolink kit. Mallinckrodt Tyco Healthcare, St. Louis MO. [15] Krohn KA, Mankoff DA, Muzi M et al. True tracers: comparing FDG with glucose and FLT with thymidine. Nucl Med Biol. 2005;32:663-71. [16] Smith-Jones PM, Solit DB, Akhurst T, Afroze F, Rosen N, Larson SM. Imaging the pharmacodynamics of HER2 degradation in response to Hsp90 inhibitors. Nat Biotechnol. 2004;22:701-6. 7