Identifying and navigating bottlenecks in the translation of novel radiopharmaceuticals: a perspective

The field of nuclear theranostics has experienced a true boost in recent years, fueled by robust scientific advances in tracer development. Clinical trials have confirmed the value of nuclear theranostics in extending survival and enhancing the quality of life for cancer patients. This success has drawn considerable interest from the pharmaceutical industry, which, in turn, has accelerated bench-to-bedside translation, leading to the approval of new theranostic radiopharmaceuticals [1, 2]. While this trend brings undeniable benefits, such as increased awareness of nuclear medicine’s role in patient care and greater patient access to innovative treatments, it has also led to a rise in hype- and profit-driven, potentially premature translations, which may ultimately fall short of their promise to improve patient outcomes.

The current pace of the field has created an overfilled translational pipeline, with many publications on “novel” tracers almost universally calling for rapid clinical translation. However, for a novel tracer to become a clinically relevant, ethically developed, scalable, and thus truly translatable new radiopharmaceutical, it must pass numerous bottlenecks. Some of these bottlenecks—related to legislation, regulations, ethics, and finances—are essential and unavoidable, and ultimately ensure the translation and production of high-quality clinical radiopharmaceuticals. However, they are oftentimes addressed very (or too) late in the translational process. Many other bottlenecks already arise early during preclinical tracer development and during the subsequent publication process. This editorial aims to provide a side-by-side exploration of these various bottlenecks in both scientific and publication processes, examining the challenges and complexities that must be navigated to achieve effective and sustainable integration of truly innovative tracers that offer clear advantages over existing approaches, into clinical practice.

Clinical Relevance: aligning scientific curiosity with clinical need

Scientific Perspective

A central criterion for impactful tracer development is the alignment of the preclinical research strategy with a genuine clinical need, with the central question to ask ourselves early in development being “are we solving the right problem – with the right tools”? Too often, radiopharmaceutical research tends toward theoretical applications of readily labelable biomolecules (such as antibodies) without stringent consideration of potential clinical impact. This "tracer development for tracer development’s sake" results in an oversupply of tracers that ideally meet technical, but not clinical, requirements. Already early in the tracer design phase, tracer concepts should be drafted in close exchange with clinical experts to address specific diagnostic or therapeutic questions with clear applications in patient care, as opposed to defining a potential clinical application based on the existence of a novel tracer. This implies an early, clear definition of a tracer's potential impact on the understanding, diagnosis, or treatment of a specific disease and subsequently substantiating this with robust preclinical data that underscore its potential to address an unmet clinical need.

Publication Perspective

From a publication standpoint, reviewers and journals play a critical role in setting standards that highlight clinical applicability. For example, the demonstration of a tracer's potential to alter diagnostic or therapeutic decision-making rather than simply showing that it is labelable or detectable in certain models should constitute a relevant criterion for acceptance for publication. Encouraging submissions that present tracers, which are explicitly designed to meet clinical demands, would help to screen out studies with marginal relevance in favor of papers that aim to address relevant medical problems.

"Me-Too" tracers: differentiating incremental changes from true innovation

Scientific Perspective

The proliferation of “me-too” tracers, particularly in areas like PSMA and FAP targeting, has led to an oversaturation of the scientific and publication landscape. A plethora of tracers with nearly identical characteristics are currently clogging the translational pipeline, without offering true advances over clinically implemented targeting concepts. Such radiopharmaceuticals are often developed in pursuit of proprietary IP via incremental structural changes compared to the established gold standards, with the aim to get a “share of the cake”, i.e. the booming theranostics market. However, such a mindset risks to not really contribute to scientific advancement or an improvement of patient care. True innovation solves a yet unsolved problem, and provides substantial improvement in tracer characteristics, such as in specificity, stability, tumor targeting, diagnostic accuracy, therapeutic efficacy, safety, cost-effectiveness etc. One example for a groundbreaking innovation in this sense has recently been published [3] and should encourage the scientific community to set a higher bar in the self-assessment whether a tracer demonstrates unique biological, diagnostic, or therapeutic benefits over established agents and thus justifies the resources for development and translation.

Publication Perspective

Journals and reviewers should vigilantly differentiate incremental improvements from significant advancements. Comparative data of “promising new tracers” with current gold-standard tracers should be a requirement, and the significant improvement of either molecular targeting or clinical utility should be explicitly demonstrated. When assessing manuscripts on “me-too” tracers, reviewers should critically evaluate whether minor changes constitute a significant scientific contribution or merely dilute the landscape, and stringently filter out redundancy to pave the way for substantial novelty that pushes the field forward.

Novelty and Originality: setting transparent criteria for advancement

Scientific Perspective

In tracer development, the space for innovation is vast, because it can range from the optimized, more cost-effective production of a radionuclide over improved labeling yields and purification protocols of radiopharmaceuticals to the whole range of improvements in tracer characteristics, preclinically and clinically. But as discussed in the previous paragraph, defining valid thresholds for novelty and originality is crucial. True innovation in tracer development should contribute to new biological insights, introduce novel target functionalities, or offer significant enhancements in clinical applicability. The validation of such improvements as novelty will necessitate a form of consensus in the scientific community on a structured, harmonized and transparent approach in experimental design, with comprehensive documentation of the parameters and outcomes. Only when reproducibility and comparability are ensured, a defined bar for originality can be set, which will then allow to direct focus and resources toward projects with genuine translational promise.

Publication Perspective

Publishers and reviewers should demand detailed comparative studies and a transparent reporting structure that comprehensively reveals the experimental design, allowing fellow researchers to assess and replicate findings and to distinguish between genuine advancement and experimental design-specific findings. This will help to establish clear performance benchmarks for novelty and thus to prioritize publication of studies that demonstrate concrete advancements, validated through rigorous experimental designs and cross-comparisons, which in turn would strengthen the claim to “translational potential”.

Target Validation: ensuring relevance and translational potential

Scientific Perspective

The appropriate validation of molecular targets represents an important and recurring challenge in radiopharmaceutical science. To qualify as relevant in the context of radiopharmaceutical development, a molecular target indispensably needs to fulfil a set of requirements. Firstly, its (over)expression should ideally be specific for a given, clinically relevant pathological process or biological context, with high stability of target expression over the course of the disease and within patient groups and no or negligible influence of standard-of-care treatment on expression levels. Secondly, target accessibility and expression density must match the physicochemical and pharmacokinetic properties of the radiopharmaceutical. More specifically, addressing intracellular targets with tracers for which there is no cellular uptake mechanism reported (aside from potential low-level diffusion), or attempting to visualize the expression of a cell surface target with 5.000–10.000 copies/cell on an immune cell subset in the tumor microenvironment using a radiolabeled antibody [4], will most likely not fulfil this requirement. Thus, target validation should transparently address to which extent disease specificity, target accessibility, and expression density are aligned with the maximum achievable detection sensitivity using a specific tracer/instrumentation combination, and if an accurate distinction of signal from background can be reasonably anticipated upon translation into a clinical setting. Preclinical studies should provide unambiguous proof that this is the case, and should provide solid evidence across multiple preclinical models, preferably including human tissue samples, to strengthen the case for clinical applicability of the targeting concept.

Of note, target validation and tracer evaluation are fundamentally different processes. Target validation is based on using readily accessible tools with high affinity and selectivity, such as radiolabeled antibodies, to investigate if a given molecular target meets all the above-mentioned requirements in the actual (patho)physiological setting of the disease, thus allowing conclusions if the development of clinically translatable tracers with optimized characteristics is scientifically and economically sound. In contrast, in tracer evaluation it is widely accepted to use cell lines transduced with the target of interest, both in vitro and in tumor xenografts, to provide initial evidence of successful targeting. However, since expression levels in such artificial systems are often much higher than the actual expression levels of the target under (patho)physiological conditions, this finding in itself does not yet allow any conclusions on potential translatability and requires rigorous additional evaluation in models reflecting the clinical situation. It is of crucial importance to clearly separate the objectives of target vs tracer validation, both in terms of experimental design and publication focus.

Publication Perspective

To enforce robust target validation, journals should emphasize the need for comprehensive target validation as a publication requirement, urging authors to provide thorough data on the biological relevance of targets. Reviewers equally should request validation evidence, focused on target density and accessibility, and, ideally, data from human tissues. Furthermore, reviewers should critically examine claims of target relevance and should insist on transparent data presentation that links the target to a defined and relevant clinical question. This scrutiny in the publication process will help to ensure that efforts and resources for tracer development are directed towards molecular targets with validated clinical relevance and thus translational value.

Ethical and Effective Use of Animal Models: Moving towards scalable dosimetry

Scientific Perspective

The preclinical evaluation of therapeutic tracers often relies on high-dose efficacy and survival studies that invariably demonstrate delayed tumor growth in transduced tumor models but have limited translational value for human use. In contrast, organ dosimetry provides the most important and translatable data for theranostic and therapeutic radiopharmaceuticals. Using immunosuppressed mice with human tumor xenografts and realistic target expression, dosimetry data can be accurately determined without requiring the full biological context of human tumors. Advances in dosimetry methods allow precise extrapolation to humans [5, 6], with the delivered organ dose (Gy/MBq) serving as a key parameter for estimating the realistically achievable therapeutic index. Toxicity assessments will remain a mainstay in preclinical safety evaluation—under the crucial condition that the therapeutic tracer cross-reacts with the corresponding mouse target and that thus, potential toxicities can be accurately depicted. However, they should focus on translationally relevant doses and include detailed evaluations of liver, kidney, and blood parameters, especially in the context of targeted alpha therapy [7]. Consistent with the 3R principles (Replacement, Reduction, Refinement), researchers should reevaluate the necessity of high-dose efficacy studies and prioritize scalable dosimetry models that better predict human outcomes.

Publication Perspective

Journals should actively promote the 3R principles in both research and publication processes and require clear justification for the choice and execution of animal studies in preclinical tracer development, focusing on ethical and translationally relevant endpoints. It is in the responsibility of reviewers to encourage authors to refine animal model usage, to focus on predictive dosimetry, and to challenge studies that fail to provide a clear translational pathway to human applications. By prioritizing studies that meet rigorous animal model justification and dosimetry scaling criteria, redundant or ethically tenuous studies that do not align with human clinical relevance can be reduced, and translational efficacy can be improved.

Data Transparency and Integrity: setting higher standards

Scientific Perspective

Poor data interpretation, overstated conclusions, and selective reporting are pervasive challenges in preclinical tracer development. A troubling trend is the tendency to declare that almost every new tracer “warrants clinical translation,” often without robust supporting evidence. This issue needs to be addressed by more rigorous self-scrutiny on the part of researchers on several levels. First and foremost, methodological rigor is essential to ensure that experiments are well-designed, reproducible, and free from bias. Additionally, for the sake of transparency, negative data should also be reported, as the omission of such findings may create a misleadingly optimistic view of a tracer’s potential. Another critical component is objectivity. Despite the personal enthusiasm that tracer developers may feel towards their results, the research community must resist the temptation to overinterpret data or draw conclusions that exceed the evidence presented. Furthermore, findings should be communicated transparently and placed in the appropriate clinical and scientific context, avoiding exaggeration or oversimplification. Finally, citing relevant literature is crucial, as it not only situates the work within the broader scientific discourse but also ensures that translational claims are substantiated and that prior contributions are fully acknowledged. By adhering to these principles, a culture of accountability and reliability can be created, improving the transition of promising tracers from preclinical studies to clinically relevant applications.

Publication Perspective

Journals and reviewers play a vital role in addressing poor data interpretation, overstated conclusions, and selective reporting in preclinical tracer development. To enforce high standards for methodological rigor, journals should require detailed protocols, transparent reporting, and the inclusion of raw data to ensure reproducibility. Reviewers, in turn, must carefully evaluate study designs, statistical methods, and the appropriateness of controls, ensuring that the conclusions are fully supported by the data. To counteract publication bias, journals should also consider the acceptance of manuscripts describing negative results, while reviewers must ensure that manuscripts present a complete and unbiased picture, including negative data where applicable. Since objectivity is crucial, reviewers should insist on neutral, evidence-based language and reject speculative or overstated claims. Moreover, both journals and reviewers should ensure that new findings are situated in an appropriate, comprehensive context. This includes demanding the comparison of new tracers to existing ones and encouraging the use of relevant, balanced citations to acknowledge prior work. By reinforcing a culture of rigorous peer review, journals and reviewers can achieve that preclinical tracer development publications provide a more balanced view of tracer performance and limitations, and thus significantly improve the reliability and impact of preclinical tracer research, which will ultimately support clinical translation efforts.

Navigating Systemic Constraints: Regulatory and logistical challenges

Scientific Perspective

The development of novel radiopharmaceuticals faces inherent translational bottlenecks that must be addressed early in the process to ensure future translatability. For example, national and international regulatory bodies demand extensive documentation to demonstrate ethics, safety, and efficacy of novel radiopharmaceuticals, with stringent approval processes mandated by organizations such as the EMA or FDA. Being aware of the required extent of compound characterization and integrating it early in preclinical tracer evaluation can greatly facilitate compilation of the investigator’s brochure (IB) and other documents for clinical translation at later stages. Additionally, the availability of radionuclides presents a significant challenge, as certain radionuclides are scarce, making them prohibitively expensive or impractical for widespread clinical use. This aspect should also be taken into account in the early development phase, for example by providing sufficient versatility in terms of chelator chemistry to accommodate several alternative radionuclides and thus avoid stalling of tracer translation due to radionuclide-related limitations. Furthermore, manufacturing and upscaling may represent critical hurdles, as the transition from small-batch, lab-scale production to GMP-compliant large-scale manufacturing is highly complex and resource-intensive. Thus, translational preclinical studies should already address this potential bottleneck and provide early evidence on the feasibility of upscaling to clinical batches. Overall, proactively addressing these challenges will aid in managing expectations and planning more effective translational pathways.

Publication Perspective

To support efficient translation based on a realistic assessment of potential hurdles, journals should prioritize manuscripts that outline plans for addressing translational challenges such as scalability, radionuclide availability, regulatory hurdles, and resource requirements. Beyond proof-of-concept data, authors should be encouraged to demonstrate how novel radiopharmaceuticals can realistically be scaled for clinical application. Enhancing awareness regulatory and logistical restraints at the early publication stage will promote realistic, practical planning, and radiopharmaceutical science can more effectively bridge the gap from preclinical research to clinical implementation.

Conclusion

The translational process for novel radiopharmaceuticals requires a holistic and critical approach to each stage of tracer development and publication. By setting high standards for clinical relevance, innovation, transparency, and ethical responsibility, existing bottlenecks can be more efficiently navigated, and truly innovative tracers can advance more rapidly towards a clear clinical purpose. Such an approach will ensure that the potential of radiopharmaceutical science for making profound contributions to patient care and the field of Nuclear Medicine can ultimately be fulfilled.

Compliance with ethical standards

Ethical approval

Not applicable to this Editorial.

Informed consent

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Conflict of interest

The author declares no conflicts of interest.