Emerging Radionuclides in a Regulatory Framework for Medicinal Products – How Do They Fit?

Recent years have seen the establishment of several radionuclides as medicinal products in particular in the setting of theranostics and PET. [177Lu]Lutetium Chloride or [64Cu]Copper Chloride have received marketing authorization as radionuclide precursor, [68Ga]Gallium Chloride has received regulatory approval in the form of different 68Ge/68Ga generators. This is a formal requirement by the EU directive 2001/83, even though for some of these radionuclide precursors no licensed kit is available that can be combined to obtain a final radiopharmaceuticals, as it is the case for Technetium-99m. In view of several highly promising, especially metallic radionuclides for theranostic applications in a wider sense, the strict regulatory environment poses the risk of slowing down development, in particular for radionuclide producers that want to provide innovative radionuclides for clinical research purposes, which is the basis for their further establishment. In this paper we address the regulatory framework for novel radionuclides within the EU, the current challenges in particular related to clinical translation and potential options to support translational development within Europe and worldwide

Emerging Radionuclides in a Regulatory Framework for Medicinal Products – How Do They Fit?

Recent years have seen the establishment of several radionuclides as medicinal products in particular in the setting of theranostics and PET. [177Lu]Lutetium Chloride or [64Cu]Copper Chloride have received marketing authorization as radionuclide precursor, [68Ga]Gallium Chloride has received regulatory approval in the form of different 68Ge/68Ga generators. This is a formal requirement by the EU directive 2001/83, even though for some of these radionuclide precursors no licensed kit is available that can be combined to obtain a final radiopharmaceuticals, as it is the case for Technetium-99m. In view of several highly promising, especially metallic radionuclides for theranostic applications in a wider sense, the strict regulatory environment poses the risk of slowing down development, in particular for radionuclide producers that want to provide innovative radionuclides for clinical research purposes, which is the basis for their further establishment. In this paper we address the regulatory framework for novel radionuclides within the EU, the current challenges in particular related to clinical translation and potential options to support translational development within Europe and worldwide

Emerging Radionuclides in a Regulatory Framework for Medicinal Products – How Do They Fit?

Recent years have seen the establishment of several radionuclides as medicinal products in particular in the setting of theranostics and PET. [177Lu]Lutetium Chloride or [64Cu]Copper Chloride have received marketing authorization as radionuclide precursor, [68Ga]Gallium Chloride has received regulatory approval in the form of different 68Ge/68Ga generators. This is a formal requirement by the EU directive 2001/83, even though for some of these radionuclide precursors no licensed kit is available that can be combined to obtain a final radiopharmaceuticals, as it is the case for Technetium-99m. In view of several highly promising, especially metallic radionuclides for theranostic applications in a wider sense, the strict regulatory environment poses the risk of slowing down development, in particular for radionuclide producers that want to provide innovative radionuclides for clinical research purposes, which is the basis for their further establishment. In this paper we address the regulatory framework for novel radionuclides within the EU, the current challenges in particular related to clinical translation and potential options to support translational development within Europe and worldwide

Radiolabeled PSMA Inhibitors

PSMA has shown to be a promising target for diagnosis and therapy (theranostics) of prostate cancer. We have reviewed developments in the field of radio- and fluorescence-guided surgery and targeted photodynamic therapy as well as multitargeting PSMA inhibitors also addressing albumin, GRPr and integrin αvβ3. An overview of the regulatory status of PSMA-targeting radiopharmaceuticals in the USA and Europe is also provided. Technical and quality aspects of PSMA-targeting radiopharmaceuticals are described and new emerging radiolabeling strategies are discussed. Furthermore, insights are given into the production, application and potential of alternatives beyond the commonly used radionuclides for radiolabeling PSMA inhibitors. An additional refinement of radiopharmaceuticals is required in order to further improve dose-limiting factors, such as nephrotoxicity and salivary gland uptake during endoradiotherapy. The improvement of patient treatment achieved by the advantageous combination of radionuclide therapy with alternative therapies is also a special focus of this review

Synthesis and tunability of abnormal 1,2,3-triazolylidene palladium and rhodium complexes

Palladation of N3-alkylated 1,2,3-triazolium salts with Pd(OAc)₂ afforded a μ²−I₂ bridged bimetallic complex [Pd(trz)I₂]₂ and monometallic bis(carbene) complexes Pd(trz)₂I₂ as a mixture of trans and cis isomers (trz = 1,2,3-triazol-5- ylidene). Addition of excess halide or modification of the palladation procedure from direct functionalization to a transmetalation sequence involving a silver intermediate allowed for chemoselective formation of the bis(carbene) complex, while subsequent anion metathesis with NaI produced the monometallic bis(carbene) complexes exclusively. Modification of the wingtip group had little influence on the metalation to palladium or rhodium(I) via transmetalation. According to NMR analysis using δC and ¹JRh−C, subtle but noticeable tunability of the metal electronic properties was identified. In addition, phenyl wingtip groups as N- substituents in the triazolylidene ligands were susceptible to cyclopalladation in the presence of NaOAc and are thus not chemically inert

Radiolabeled PSMA Inhibitors

Simple Summary Prostate cancer remains one of the leading causes of cancer death in men worldwide. Despite the recent success in the development and clinical application of radiopharmaceuticals targeting the prostate-specific membrane antigen (PSMA) for diagnosis and endoradiotherapy of prostate cancer, more research is ongoing to further investigate and improve patient care and quality of life. Herein, an overview of novel developments and applications for small molecule and low-molecular weight radiolabeled PSMA inhibitors with an outlook to clinical translation is given. PSMA has shown to be a promising target for diagnosis and therapy (theranostics) of prostate cancer. We have reviewed developments in the field of radio- and fluorescence-guided surgery and targeted photodynamic therapy as well as multitargeting PSMA inhibitors also addressing albumin, GRPr and integrin alpha(v)beta(3). An overview of the regulatory status of PSMA-targeting radiopharmaceuticals in the USA and Europe is also provided. Technical and quality aspects of PSMA-targeting radiopharmaceuticals are described and new emerging radiolabeling strategies are discussed. Furthermore, insights are given into the production, application and potential of alternatives beyond the commonly used radionuclides for radiolabeling PSMA inhibitors. An additional refinement of radiopharmaceuticals is required in order to further improve dose-limiting factors, such as nephrotoxicity and salivary gland uptake during endoradiotherapy. The improvement of patient treatment achieved by the advantageous combination of radionuclide therapy with alternative therapies is also a special focus of this review

Carbon ion radiotherapy: impact of tumor differentiation on local control in experimental prostate carcinomas

Abstract Background To summarize the research activities of the “clinical research group heavy ion therapy”, funded by the German Research Foundation (DFG, KFO 214), on the impact of intrinsic tumor characteristics (grading, hypoxia) on local tumor control after carbon (12C-) ion- and photon irradiations. Methods Three sublines of syngeneic rat prostate tumors (R3327) with various differentiation levels (highly (-H), moderately (-HI) or anaplastic (-AT1), (diameter 10 mm) were irradiated with 1, 2 and 6 fractions of either 12C-ions or 6 MV photons using increasing dose levels. Primary endpoint was local tumor control at 300 days. The relative biological effectiveness (RBE) of 12C-ions was calculated from TCD50-values (dose at 50% tumor control probability) of photons and 12C-ions and correlated with intrinsic tumor parameters. For the HI-subline, larger tumors (diameter 18 mm) were irradiated with either carbon ions, oxygen ions or photons under ambient as well as hypoxic conditions to determine the variability of the RBE under different oxygenation levels. In addition, imaging, histology and molecular analyses were performed to decipher the underlying mechanisms. Results Experimental results revealed (i) a smaller variation of the TCD50-values between the three tumor sublines for 12C-ions (23.6 - 32.9 Gy) than for photons (38.2 - 75.7 Gy), (ii) steeper dose-response curves for 12C-ions, and (iii) an RBE that increased with tumor grading (1.62 ± 0.11 (H) vs 2.08 ± 0.13 (HI) vs 2.30 ± 0.08 (AT1)). Large HI-tumors resulted in a marked increase of TCD50, which was increased further by 15% under hypoxic relative to oxic conditions. Noninvasive imaging, histology and molecular analyses identified hypoxia as an important radioresistance factor in photon therapy. Conclusions The dose-response studies revealed a higher efficacy of 12C-ions relative to photon therapy in the investigated syngeneic tumor model. Hypoxia turned out to be at least one important radioresistance factor, which can be partly overridden by high-LET ion beams. This might be used to increase treatment effectiveness also in patients. The results of this project served as a starting point for several ongoing research projects

Preclinical characterization of 18F-D-FPHCys, a new amino acid-based PET tracer

The imaging potential of a new F-18-labelled methionine derivative, S-(3-[F-18]fluoropropyl)-d-homocysteine (F-18-D-FPHCys), and its selectivity for amino acid transporter subtypes were investigated in vitro and by imaging of human tumour xenografts. Expression of members of the system L (LAT isoforms 1-4 and 4F2hc) and ASCT (ASCT isoforms 1 and 2) amino acid transporter subclasses were assessed by quantitative real-time PCR in four human tumour models, including A431 squamous cell carcinoma, PC3 prostate cancer, and Colo 205 and HT-29 colorectal cancer lines. The first investigations for the characterization of F-18-D-FPHCys were in vitro uptake studies by comparing it with [1-C-14]-l-methionine (C-14-MET) and in vivo by PET imaging. In addition, the specific involvement of LAT1 transporters in F-18-D-FPHCys accumulation was tested by silencing LAT1 mRNA transcription with siRNAs. To determine the proliferative activity in tumour xenografts ex vivo, Ki-67 staining was used as a biomarker. A431 cells showed the highest F-18-D-FPHCys uptake in vitro and in vivo followed by Colo 205, PC3 and HT-29. A similar pattern of retention was observed with C-14-MET. F-18-D-FPHCys retention was strongly correlated with LAT1 expression both in vitro (R (2) = 0.85) and in vivo (R (2) = 0.99). Downregulation of LAT1 by siRNA inhibited F-18-D-FPHCys uptake, demonstrating a clear dependence on this transporter for tumour uptake. Furthermore, F-18-D-FPHCys accumulation mirrored cellular proliferation. The favourable properties of F-18-D-FPHCys make this tracer a promising imaging probe for detection of tumours as well as for the noninvasive evaluation and monitoring of tumour growth.© 2012, Springer

Improved detection of regional melanoma metastasis using 18F-6-fluoro-N-[2-(diethylamino)ethyl] pyridine-3-carboxamide, a melanin-specific PET probe, by perilesional administration

The efficacy of differing routes of administration of 18F-6-fluoro-N-[2-(diethylamino)ethyl] pyridine-3-carboxamide (18F-MEL050), a new benzamide-based PET radiotracer for imaging regional lymph node metastasis in melanoma, was assessed. Methods: B16-Black/6 metastatic melanoma cells harboring an mCherry transgene were implanted into the left-upper-foot surface of 49 C57 Black/6 mice as a model of popliteal lymph node (PLN) metastasis. Ultrasound scanning of the left PLN was performed at baseline and in combination with 18F-MEL050 PET on days 5, 9, and 14. Mice were divided into 2 groups to compare the results of tracer administration either subcutaneously at the tumor site (local) or in the lateral tail vein (systemic). After PET on each imaging day, 5 mice per group—including any with evidence of metastasis—were sacrificed for ex vivo validation studies including assessment of retained radioactivity and presence of the mCherry transgene as a surrogate of nodal tumor burden. Results: Nine mice were judged as positive for PLN metastasis by ultrasound at day 5, and 8 PLNs were positive on 18F-MEL050 PET, 3 after systemic and 5 after local administration. Ex vivo analysis showed that ultrasound correctly identified 90% of positive PLNs, with 1 false-positive. 18F-MEL050 PET correctly identified 60% of positive PLNs after systemic administration and 100% after local administration with no false-positive results by either route. The average node-to-background ratio for positive PLNs was 6.8 in the systemic-administration group and correlated with disease burden. In the local-administration group, the mean uptake ratio was 48, without clear relation to metastatic burden. Additional sites of metastatic disease were also correctly identified by 18F-MEL050 PET. Conclusion: In addition to its potential for systemic staging, perilesional administration of 18F-MEL050 may allow sensitive and specific, noninvasive identification of regional lymph node metastasis in pigmented malignant melanomas. © 2011, Society of Nuclear Medicin