Abstract
Cancer theranostics is an emerging and exciting field in nuclear medicine, whereby suitably designed radionuclide carriers, after injection to patients, seek and specifically interact with biomolecular targets overexpressed on cancer cells. When a diagnostic radionuclide is applied, molecular imaging with SPECT (gamma emitter) or PET (positron emitter) will reveal tumor lesions, allowing for initial diagnosis and assessment of disease spread and progression. Hence, molecular imaging represents a reliable tool for patient stratification, dosimetry and planning of therapy that follows next with the respective therapeutic radionuclide (beta, Auger electron, or alpha emitter) carrier in an integrated patient-tailored approach. In this way, patients are spared from ineffective and toxic therapies that only impair quality of life without any tangible benefit. Several recent examples have demonstrated the feasibility and efficacy of this strategy. Thus, the advent of radiolabeled somatostatin analogs in the management of neuroendocrine tumors on one hand, and the successful application of prostate-specific membrane antigen inhibitors to diagnose and combat prostate cancer on the other, are two elegant paradigms of this approach.
In this chapter, we shall discuss important issues pertaining to the design and preclinical evaluation of peptide-based radioligands, focusing on compound examples developed in our center. The steps to be followed for clinical translation of selected analogs will be also briefly described. Emphasis will be given on the significance of pilot proof-of-principle studies in a small number of patients to guide further efforts toward drug development and registration.
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22.1 Introduction
Advances in molecular biology and basic cancer research have documented the expression of “footprint” biomolecules on the surface of tumor cells, as for example antigens, peptide receptors, or enzymes [1,2,3]. This finding offers the opportunity to direct the respective radionuclide carriers to these biomolecular targets on cancer sites after injection to patients. Accordingly, radiolabeled antibodies, peptides or enzyme inhibitors will deliver gamma (e.g., 99mTc, 111In) or positron emitters (e.g., 68Ga, 64Cu) to tumor sites with a high specificity for SPECT and PET imaging, respectively. Molecular imaging consequently represents a powerful tool for initial diagnosis, assessment of disease spread and patient stratification for the step which may follow next, namely, radionuclide therapy. The latter is accomplished by applying the same molecular probe which this time will deliver cytotoxic payloads to tumor sites by means of particle-emitting radionuclides, such as Auger electron (111In), beta (177Lu, 64/67Cu), or alpha (213Bi, 225Ac) emitters. Again, molecular imaging with the respective diagnostic counterpart will be instrumental not only for the preceding dosimetry and therapy planning but most importantly for monitoring therapeutic responses and disease progression. Hence, diagnosis and therapy—theranostics—may be elegantly combined in the management of cancer patients allowing for a personalized approach with maximized benefits. Furthermore, molecular imaging is essential for sparing patients from ineffective and toxic therapies which will only deteriorate quality of life without offering any tangible benefits [4,5,6,7,8,9,10].
All abovementioned classes of compounds have shown successful application paradigms in clinical nuclear medicine, but in the current chapter we shall focus on radiolabeled peptide analogs [3]. Peptides are native substances regulating a plethora of functions in the human body via specific interaction with protein receptors located on the cell membrane of target cells. Peptide receptors belong to the superfamily of G-protein coupled receptors (GPCRs) characterized by seven transmembrane domains and are essential for the transduction of extracellular messages within the cell [11, 12]. Most drugs of classical pharmacology are directed against GPCRs. Thus, native peptides as well as synthetic anti-GPCR drugs (peptidic or not) represent an abundant source of chemical entities that may serve as motifs for the development of radionuclide peptide-like carriers directed to GPCRs on tumors [13,14,15].
Amongst the attractive features of peptides for clinical application, one can cite their low immunogenicity, fast reaching the target after injection, rapid clearance from the body, most often preferably via the kidneys and the urinary system. Moreover, peptides have turned out to be resilient during chemical and radiochemical manipulations, and can be synthesized and modified with relative ease, as compared with other vectors, as for example antibodies. A major problem in their use is associated with their notorious propensity to proteolytic degradation mainly by a class of enzymes hydrolyzing peptide bonds, that is, peptidases (vide infra). Further concerns during the development of peptide analogs for use in nuclear medicine are the high-density expression of the GPCR target in physiological tissues and organs of the body as well as the adverse effects elicited in patients after injection of peptide agonists and activation of their cognate receptor [3, 15, 16].
Peptide-based radionuclide carriers used in nuclear medicine usually comprise the following major segments (Fig. 22.1): the peptide fragment (A), recognizing and interacting with the cognate GPCR target on cancer cells, the metal chelator (C) binding the radiometal of choice (D) while coupled to the peptide chain either directly or via the linker or spacer (B), keeping the metal-chelate and the peptide segments apart from each other and often serving as a pharmacokinetic modifier [8, 15, 17, 18].
Radiolabeled bioconjugate comprising the peptide part (A), the linker (B), and the chelator (C) stably binding the radiometal (D); the radiopeptide localizes on tumor sites through specific interaction with the GPCR target residing on tumor cells
22.2 Peptides and GPCR Targets on Tumors
The rationale behind the clinical success of theranostic radiopeptides in the management of human tumors relies one hand on the high density and high incidence expression of the cognate GPCR target on tumor cells and on the other on the lack or minimal expression of the target in healthy surrounding tissue [3]. The list of Table 22.1 includes major peptide families used as motifs in the development of theranostic radiopeptides and the tumor classes where they are overexpressed.
Thus far, the research activities of Molecular Radiopharmacy at NCSR “Demokritos” (MR-NCSRD) have been directed toward the development and preclinical screening of radiopeptides from the somatostatin, bombesin (BBN)/gastrin-releasing peptide (GRP), cholecystokinin (CCK)/gastrin and neurotensin (NT) peptide families (Table 22.1), for eventual clinical assessment in patients. The problems and difficulties during this effort will be briefly discussed in individual sections in this chapter.
Although the GPCR targets of the above-mentioned peptide families are abundantly present in the tumors indicated in the table, they are also physiologically expressed in certain tissues and organs of the body complicating the application of diagnosis and therapy. Thus, the somatostatin subtype 2 receptor (SST2R) [19,20,21,22,23] and the gastrin-releasing peptide receptor (GRPR) [24,25,26,27,28,29,30,31] are expressed in high numbers in the human pancreas, the cholecystokinin subtype 2 receptors (CCK2Rs) [32,33,34,35,36,37,38] are abundantly found in the gastric mucosa and neurotensin subtype 1 receptors (NTS1Rs) [39,40,41,42,43,44] in the intestines. Moreover, radiopeptide excretion via the kidneys may be delayed in some cases due to tubular reabsorption mechanisms, imposing dosimetric restrictions for radionuclide therapy [45].
These handicaps may be addressed by structural modifications of the peptide chain and/or the linker. Other approaches have been adopted as well. For example, faster washout of BBN-like radiopeptide agonists from physiological GRPR-rich organs, such as the pancreas, can be achieved by the application of GRPR-antagonists instead [46, 47]. Such a switch from agonist- to antagonist-based radiopeptides offers the additional advantage of circumventing the problem of adverse effects elicited after GRPR activation. Finally, reduction of renal accumulation can be effectively tackled by applying kidney protection regimens. For example, infusion of the plasma expander gelofusine alone or in combination with basic amino acid cocktails has been shown to significantly reduce the renal uptake of anti-SST2R theranostic radiopeptides [45, 48, 49].
22.3 Radiometals and Their Chelators in Cancer Theranostics
A list of the most clinically relevant radiometals employed in cancer theranostics with the aid of radiopeptides is provided in Table 22.2, including subgroups of radiometals for SPECT, PET and for radionuclide therapy, along with their nuclear characteristics and modes of production [17, 18, 50]. Radiometals used in MR-NCSRD facilities are: 99mTc, 111In and 177Lu; for the development of 68Ga-radiopeptides for PET, we have used the 67Ga surrogates (t1/2: 78.3 h, decay: EC/100%—887.7, 393.5, 184.6, 93.3/keV, cyclotron produced).
The pre-eminent diagnostic radionuclide in nuclear medicine has been and still is 99mTc, owing to its excellent nuclear properties, wide and cost-effective availability in high specific activity and high purity via commercial 99Μο/99mTc generators [51,52,53]. The versatile coordination chemistry of 99mTc, seen often both as a blessing and a curse, offers exciting options for the development of new chelating systems and for “revisiting” existing ones for molecular imaging applications. The 99mTc-based peptide radioligands developed at MR-NCSRD for diagnosis of human tumors with SPECT and SPECT/CT have involved acyclic tetraamines for binding of the radiometal. Such tetraamine donor arrangements have been shown to form monocationic octahedral trans-dioxo-Tc-chelates, which are hydrophilic and in vivo robust (Fig. 22.2) [54, 55]. Several somatostatin, BBN, gastrin and NT analogs have been coupled to 6-R-1,4,8,11-tetraazaundecane (R: a bifunctional anchor, such as a carboxylic group) and labeled with 99mTc. During biological evaluation in preclinical models a few analogs displayed excellent profiles qualifying for further clinical testing as well. It should be noted that due to the “lanthanide contraction” the atomic radii of technetium and its third row congener rhenium are almost identical and their compounds exhibit similar physicochemical and structural characteristics [56]. Rhenium, besides serving as a surrogate for technetium during chemical investigations, is of special relevance to nuclear medicine by means of two important therapeutic radionuclides, 186Re (t1/2: 90.6 h, decay: β− 2120 keV/γ 155 keV, reactor produced) and 188Re (t1/2: 17 h, decay: EC/100% - 887.7, 393.5, 184.6, 93.3 /keV, 188W/188Re generator) [57]. This fact provides the exciting prospect of routine preparations of matched 99mTc/diagnostic–186/188Re/therapeutic radiopharmaceutical pairs in hospital radiopharmacy departments.
Bifunctional chelators used for labeling peptides with 99mTc (acyclic tetraamines) and the trivalent metals 111In, 177Lu and 67/68Ga at MR-NCSRD (the polyamino-polycarboxylic-macrocycles DOTA, NOTA and their bifunctional versions)
The trivalent radionuclides listed in Table 22.2 form stable complexes with the polyamino-polycarboxylic-macrocycles DOTA (1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid), NOTA (1,4,7-triazacyclononane-N,N′,N″-triacetic acid) and their bifunctional versions (Fig. 22.2) [17, 18, 50]. The majority of the peptide analogs developed at MR-NCSRD have been derivatized with the so called universal chelator DOTA, because it provides the unique option of labeling peptides with 67/68Ga (for PET), 111In (for SPECT) and 177Lu (for radionuclide therapy) without the need for developing analogs carrying a different chelator for each application. It should be noted however that, owing to the differences in the coordination chemistries across these radiometals, the forming radiopeptides may differ in their charge, lipophilicity and other physicochemical features. As a result, significant differences may be observed in several biological responses, including receptor affinity, metabolic stability and pharmacokinetics [58,59,60]. The use of theranostic radionuclides (e.g., 64Cu) [61, 62], or theranostic radioisotopes of the same element (e.g., 149/152/155/161Tb, or 44/47Sc) [63,64,65] represents an attractive alternative in this respect. Selection of the appropriate radionuclide for each application depends on several important factors, such as advantageous nuclear characteristics, availability and cost [50].
22.4 Metabolic Stability of Radiopeptides: The Pep-Protect Concept
A major hurdle in the development of peptide drugs, including peptide radiopharmaceuticals, is their susceptibility to enzymes hydrolyzing the peptide bond, known as peptidases [13, 14]. Peptidases are abundantly present in the biological milieu and are found in the blood solute, the extracellular matrix, within cells, as well as anchored on epithelial cell membranes in many organs and tissues of the body. Omnipresent peptidases are actually orchestrating the action of native peptides, cooperating with other enzymes to release the active peptide from precursor molecules and degrading it thereafter to biologically inert fragments [66]. In nuclear medicine applications, the peptide radiopharmaceutical is intravenously injected to patients and rapidly—within minutes—reaches the GPCR-targets on tumor sites owing to its small size. The integrity of the radiopeptide within this time window is very essential for its “safe” arrival to tumor sites and subsequent uptake by cancer cells. Such integrity may be seriously challenged by peptidases encountered by the radiopeptide on the way to the target, which may act quite fast and devastatingly (Fig. 22.3) [67].
(a) Upon entry into the blood stream, a biodegradable radiopeptide is attacked by peptidases, such as wall-anchored neprilysin (green) and/or angiotensin-converting enzyme in the solute (yellow). Thus, only a few intact radiopeptide molecules are delivered to tumor sites, compromising tumor uptake. (b) Coinjection of suitable peptidase(s)-inhibitor(s), such as phosphoramidon, or thiorphan (pink) and/or lisinopril (turquoise), leads to an increase of the number of intact radiopeptide molecules that will be delivered to tumor sites, enhancing the localization of the radiolabel to malignant lesions. This will eventually translate into improved imaging quality and/or therapeutic index
In fact, several studies using in vitro incubation of radiopeptides in plasma or serum have shown the swift action of peptidases found in the blood solute, such as angiotensin-converting enzyme (ACE) [66, 68, 69]. Recently, the leading role of neprilysin (NEP) in the rapid in vivo degradation of radioligands originating from numerous peptide families has been revealed by chromatographic analysis of blood samples collected after injection in the living organism [67]. Interestingly, the above-mentioned central role of NEP had been largely disregarded, because its presence in plasma or serum is minimal. Instead, NEP is anchored on vasculature walls and epithelial cell membranes of several tissues and organs of the body, such as lungs, intestines and kidneys, in high local concentrations [70, 71]. The fast degrading action of NEP, ACE and/or other proteases, encountered by the radiopeptide after entering the circulation allows only a small portion of the intact analog to reach and eventually interact with the GPCR target on tumor sites. Hence, tumor uptake is compromised, directly impairing image quality and/or therapeutic index.
One way to address the problem of metabolic instability is via structural modifications of the peptide sequence, such as replacements of key amino acids by their D- or beta-congeners or by other synthetic residues, cyclization, reduction or methylation of known cleavage sites, or even substitution of peptide bonds by their 1,2,3-triazole isosteres [13, 14, 72]. All these methods are time- and resources-intensive. At the same time, improvements of metabolic stability by structural interventions very often occur at the cost of other biological characteristics, important for the optimal performance of radiopeptide analogs, such as receptor affinity, internalization rate and pharmacokinetics.
We have recently proposed the co-administration of a single or twin protease inhibitor with the radiopeptide to “protect” it from the attacking proteases (NEP and/or ACE) and “serve” for safer delivery at tumor sites, the so-called pep-protect concept (Fig. 22.3) [67]. We have shown that administration of a NEP-inhibitor (or a precursor thereof), such as phosphoramidon [73], thiorphan [70], or sacubitrilat [74], can stabilize biodegradable radiopeptides from the somatostatin [67], BBN [60, 72, 75,76,77,78,79,80], gastrin [66, 81,82,83,84] and NT [69] families, translating into notable increases of tumor targeting in experimental animal models. In a few cases, combination of a NEP and an ACE-inhibitor, such as lisinopril, is required for maximum effect [69, 82, 83]. This simple and elegant concept warrants further validation in the clinic. The availability of registered and over-the-counter NEP [70, 74] and ACE [85] inhibitors that have been used for years for a series of medical conditions is a valuable asset in this respect. It should be noted that the first promising results on the efficacy and safety of the pep-protect approach have been very recently reported for radiolabeled gastrin in a small number of medullary thyroid carcinoma patients (MTC) [86]. These results will pave the way for broader application of the pep-protect concept in nuclear oncology.
22.5 Radiopeptide Agonists and Antagonists
The first peptide motifs used for the development of peptide radiopharmaceuticals were native peptides, acting as agonists at their cognate receptors on target cells and thereby regulating several functions of the body. Accordingly, the synthetic cyclic octapeptide somatostatin analog octreotide and its derivatives targeting the SST2R on neuroendocrine tumor (NET) cells preserve the ability of the parent hormone to induce the SST2R internalization after binding and to transduce pharmacological responses further within the cell [87]. The ability of radioagonists to internalize has long been considered as an essential prerequisite for high uptake and prolonged retention of radiopeptides on tumor sites, enhancing diagnostic signal and therapeutic responses [88]. Surprisingly though, radiolabeled SST2R-antagonists showed significantly higher in vitro uptake in target cells and in experimental tumors in animal models [89, 90]. It was shown that these analogs were able to bind to a significant larger SST2R population (both in active and inactive state) on target cells remaining bound on the cell surface for long periods of time. Another unexpected feature of SST2R radioantagonists was their notably faster clearance from physiological tissues compared to agonists. All above-mentioned clinically attractive qualities were subsequently demonstrated in patients as well [47].
Unlike somatostatin which exerts inhibitory effects on target cells, other native peptides after binding and activation of their cognate receptor elicit potent pharmacological responses mainly in the gut and the nervous system [91,92,93]. Accordingly, intravenous administration of even small amounts of such peptides and their analogs may turn out to be very unpleasant and even dangerous to patients. For example, during clinical testing of BBN-like radioligands in prostate cancer patients, severe effects from the gastrointestinal system were recorded raising serious biosafety concerns in the nuclear medicine community [94]. It should be added that several GPCR agonists in addition exert proliferative action on cancer cells. Consequently, large libraries of synthetic GPCR antagonists have been developed in previous decades as anticancer drugs [95]. This plethora of well-established motifs represents an invaluable asset to radiopharmacists engaged in the design of antagonist-based radiopeptides. Usually, truncation of C-terminal residues and other chemical manipulations, like alkylamidation or esterification of the C-terminal carboxylic group, has proven to be an efficient means to generate receptor-antagonists from agonist precursors.
In recent years, a wide range of radiolabeled GRPR antagonists have been introduced as potential theranostic agents in the management of prostate and breast cancers with relative success [46]. In most cases, prolonged tumor retention and rapid background clearance could be established both in animal models and in humans. None of the adverse effects elicited by the administration of BBN-like radioligands was observed, further favoring the application of antagonists in the clinic. It should be noted that antagonists display better metabolic stability and are more subtype selective compared to agonists too. A list of the major GPCR-radioagonists and antagonists developed at MR-NCSRD is shown in Table 22.3, divided by receptor target [46, 77, 82, 84, 96,97,98,99,100,101,102,103,104,105,106,107,108,109,110,111,112,113,114,115,116,117,118,119,120,121,122,123,124,125,126,127,128,129,130,131,132,133,134,135,136].
It is interesting to mention as well recent experience at MR-NCSRD from the gastrin and NT radioligands. Gastrin analogs elicit adverse effects after intravenous injection to patients, which have been well-known to clinicians from the broadly applied provocative pentagastrin test [91]. Nevertheless, a wide range of radiolabeled CCK2R-radiotracers have been developed over the years, a few of which have been clinically tested [115,116,117]. A non-peptidic CCK2R-radioantagonist, 99mTc-DGA1 has been recently introduced by us in a head-to-head comparison with the clinically tested agonist 99mTc-Demogastrin 2, showing promising qualities for targeting CCK2R-positive lesions in MTC patients [123]. Further studies with peptide−/peptidomimetic-based CCK2R-radioantagonists will reveal potential benefits of their use compared to agonists. Several efforts have also been directed toward the development of NT-based radiopeptides to target NTS1R-positive tumors, such as pancreatic ductal adenocarcinoma (PDAC), or small-cell lung cancer (SCLC), with very moderate success thus far. A major handicap of NTS1R-directed radiopeptides is related to the very poor metabolic stability of NT and its analogs in vivo, the loss of internalization capability of structurally modified analogs thereof with enhanced stability and the often high kidney retention. We have shown first promising results for clinical translation by the application of a 99mTc-labeled NT(8–13) analog in combination with the pep-protect concept [118,119,120,121,122]. By minimal structural interventions and protease-inhibition regimens, we could observe preservation of full internalization capacity of the radiotracer in NTS1R-positive cells and stabilization in peripheral mice blood, translating into high uptake in experimental NTS1R-positive tumors and rapid background clearance in mice [69]. Recently, a non-peptidic NTS1R-antagonist has been used as a motif for the generation of a library of radiolabeled analogs for cancer theranostics. Surprisingly, these agents displayed high internalization rates in target cells despite their antagonistic profile during functional assays, such as Ca2+-mobilization. The clinical value of this class of compounds remains to be confirmed [124,125,126].
22.6 Radiopeptide Candidates for Clinical Translation
The preclinical evaluation of new radiopeptides in cell and animal models is an essential step to identify best candidates for translation in patients [127]. Proof-of-principle studies are indeed very crucial to verify that the promising profile of a peptide radioligand acquired in mice can accurately depict its actual performance in cancer patients. Discrepancies may occur from interspecies differences at both the molecular and the macroscopic levels [128, 129]. For example, newly developed radioligands may be able to distinguish between the mouse and the human receptor target and thus, uptake and clearance from tissues physiologically expressing the receptor may differ. On the other hand, tumor induction, localization and propagation in mice models are distinctly different than spontaneous carcinogenesis events occurring in patients. Furthermore, the rate of several physiological functions vary between mice and men, partly due to differences of body weight, eventually affecting bioavailability, tumor uptake and background clearance. Accordingly, results from proof-of-principle studies in a small number of patients are necessary for first assessments of a new agent’s clinical value, qualifying or disqualifying it for broader clinical validation and potentially for subsequent radiopharmaceutical development [130]. The last step is expected to last for years, is highly costly and requires considerable managerial and regulatory expertise which is usually provided by pharmaceutical industry. Hence, pilot studies are invaluable in cutting down costs, time and efforts to the minimum, by addressing translational concerns and further narrowing down choices to justifiable candidates.
Until recently, license for performing pilot translational studies with diagnostic peptide-radioligands required approval by the clinical center’s ethical committee after submission of a summary of the compound specifications. The latter included information on the synthesis and radiolabeling of the new agent, along with data on its efficacy during preclinical testing in cells and mice models expressing the GPCR target. Information on biosafety practically comprised acute single dose toxicity study in one animal species, usually mice. At a later stage, approval of the clinical protocol was additionally requested from national authorities. Under the latter status, we were able to get official clearance and perform first translational studies of the somatostatin-based 99mTc-Demotate 1 in NET patients and the neurotensin-based 99mTc-Demotensin 6 in pancreatic, lung and other type cancer patients in cooperation with the University Clinics, Innsbruck, Austria [112, 113, 118]. Likewise, pilot studies have been conducted for the gastrin-based 99mTc-Demogastrin 2 applying SPECT/CT initially at the University Clinics Marburg in Germany [117] and subsequently at Erasmus MC, Rotterdam, The Netherlands (Table 22.3) [115, 116]. Soon thereafter in an increasing number of EU countries, starting with the UK, approvals required much more detailed and thorough information on new compounds of GMP grade, as for example more extended toxicology studies. We had the opportunity to follow the newly imposed regulations during a pilot study on the BBN-like radiotracer 99mTc-Demobesin 4 in a small number of prostate cancer patients in St. Bartholomew’s Hospital, London, UK [99]. The compilation of all necessary efficacy and safety data as well as the availability of sufficient amounts of GMP-grade tracer required strong support from a sponsor, in this case “Cancer Research UK.”
Clearly, in most EU countries, regulations for clinical studies have been becoming stricter over recent years, requiring license not only from ethical committees of clinical centers, but also from national or even from European authorities, such as European Medicines Agency (EMEA), especially in case of multicenter clinical trials. Consequently, both high-quality GMP-grade radiotracers and extensive efficacy and safety documentation have become mandatory [130,131,132]. At the same time, in a few EU countries, it is still possible to carry out pilot studies with new compounds locally in a small number of patients, under certain provisions. For example, in Germany, the decision to conduct a diagnostic peptide-radioligand proof-of-principle study can be based on the opinion of the referring oncologist as the best choice for the patients’ respective clinical conditions. The new agent should be administered in compliance with the German Medicinal Products Act (section 13, subsection 2b), the 1964 Declaration of Helsinki, and the responsible regulatory body and under the compassionate-use clause of the German Medicinal Products Act (Federal Institute for Drugs and Medical Devices, “Compassionate use” programs, http://www.bfarm.de/EN/Drugs/licensing/clinicalTrials/compUse/_node). Following this pathway, we have recently performed such clinical studies in Bad Berka with two promising diagnostic 68Ga-labeled GRPR-antagonists, 68Ga-SB3 [46] and 68Ga-NeoBOMB1 [133], and PET/CT in a small number of prostate and breast cancer patients with very positive outcomes. Accordingly, 68Ga-SB3 is further evaluated in Erasmus MC, Rotterdam, The Netherlands, in early stage therapy naïve prostate cancer patients [134]. It should be noted that positive results on 68Ga-NeoBOMB1 in prostate cancer patients are being further acquired in Erasmus MC, Rotterdam, The Netherlands, as well as in gastrointestinal stromal tumor (GIST) patients at Innsbruck University Hospital, Austria [135]. These results have attracted the interest of the private sector, currently supporting the performance of multi-center clinical studies aiming at radiopharmaceutical development and registration [136].
The fruitful Athens (design, preclinical) ⇔ Bad Berka (clinical) interaction: Baum’s (tree’s) branches reaching out as far as Athens to interact with the local owl group
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Acknowledgments
We wish to thank so many colleagues and friends who have been supporting us in a multitude of ways since our early days at MR-NCSRD. Special thanks to Prof. H. Maecke (University Hospital Basel, Switzerland), who first initiated us in the field of radiopeptides, Prof. J.C. Reubi (Institute of Pathology, University of Berne, Switzerland) for excellent cooperation and inspiring discussions on exciting aspects of GPCR pharmacology, Prof. C. Decristoforo (University Hospital Innsbruck, Austria) and Prof. S. Mather (St. Bartholomew’s Hospital, London, UK) for their cooperation in translational studies of our first products. Special thanks to Prof. M. de Jong and her team at Erasmus MC, Rotterdam, for a most fruitful cooperation for more than 20 years now and of course, Prof. E. P. Krenning (currently at Cyclotron Rotterdam BV, Erasmus MC), who has generously, firmly and unfailingly supported us in so many ways all this time. Special thanks as well to PiChem (Gratz, Austria) for a long and enduring cooperation and reliable provision of excellent quality peptide and peptidomimetic analogs.
Last but not least, we wish to thank Prof. Baum, Richard, for his enthusiastic inspiration of the clinical translation of two very important GRPR-antagonist-based 68Ga-radiotracers for prostate and breast cancer diagnosis with PET/CT (Fig. 22.4). Richard, we know you since 2000 when you were visiting Greece within a COST Meeting. We then showed you our preclinical results of the first 99mTc-based GRPR-antagonist, 99mTc-Demobesin 1, in PC-3 tumor-bearing animals. Since that moment, you have been reminding us on every opportunity to provide you with the 68Ga-version of 99mTc-Demobesin 1 the soonest possible and you would not let go – fortunately. Your strongly expressed willingness to test such agent in prostate and breast cancer patients applying PET/CT in Bad Berka, has been the impetus for the successful development of 68Ga-SB3 and 68Ga-NeoBOMB1. Eventually, the first clinical testing of both 68Ga-SB3 and 68Ga-NeoBOMB1 was indeed performed by you and your team in Bad Berka. Thank you!.
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Nock, B.A., Maina, T. (2024). Theranostic Radiopeptides in Nuclear Oncology: Design, Preclinical Screening, and Clinical Translation. In: Prasad, V. (eds) Beyond Becquerel and Biology to Precision Radiomolecular Oncology: Festschrift in Honor of Richard P. Baum. Springer, Cham. https://doi.org/10.1007/978-3-031-33533-4_22
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