The Evolution of Nuclear Medicine from Unclear to ‘Precision’ Medicine

By Nosheen Fatima

Affiliations

1. Department of Nuclear Medicine and Theranostics, Comprehensive Cancer Centre, Dow University of Health Sciences, Karachi, Pakistan

doi: 10.29271/jcpsp.2025.08.945

The transition from unclear medicine to theranostics in nuclear medicine represents a profound evolution in the field. Nuclear medicine, in its infancy (1950s-1970s), began with the invention of the Anger camera by Hal O. Anger in 1957,¹ but routine nuclear medicine imaging only became widespread in the 1960s. Nuclear medicine was often termed as unclear medicine due to the initial limitations of image quality and resolution. Technological advancements led to the development of gamma cameras and later SPECT by David Kuhl and Roy Edwards in 1963,² and the first multi-slice cylindrical array PET scanner was introduced in 1974 by a group of scientists, with Michael Ter-Pogossian credited as the father of the PET scanner.³ These modalities offered a more detailed view of physiological processes, reducing the uncertainty typical of early nuclear medicine techniques. The combination of PET and CT scanners was realised in the 1990s. The first PET–CT system was constructed by David Townsend (at the University of Geneva) and Ronald Nutt with help from colleagues⁴ and was commercially installed in 2001.⁵ The introduction of PET/CT and SPECT/CT marked a turning point in nuclear medicine by merging functional imaging with CT-based attenuation correction and anatomical localisation, thereby addressing the major limitation of poor resolution. This integration significantly improved the spatial resolution of images, allowing for more precise disease localisation, enhanced diagnostic accuracy, and  improved  treatment  planning.

PET/CT is invaluable in oncology for diagnosing, staging, and monitoring treatment responses. Beyond cancer, it holds potential for applications in neurological and cardiovascular diseases due to superior diagnostic accuracy based on combined functional and morphological information, but faces challenges related to cost, availability, and complexity. The integration of radiogenomics with PET/CT could revolutionise personalised medicine and offer a new era for researchers. It enables correlation between imaging phenotypes identified through PET/CT and genomic markers, enhancing the understanding of disease mechanisms.⁶

The term theranostics, coined by John Funkhouser, was officially emerged in 1998.⁷ However, the underlying concept of combining imaging and treatment using similar radiolabelled molecules existed long before the term itself. For instance, oral radioactive Iodine-¹³¹ therapy (RAI-¹³¹) has been used for decades to treat toxic goitre and well-differentiated thyroid cancer. The modern concept of theranostics represents a groundbreaking advancement in the convergence of therapy and diagnosis, transforming the landscape of personalised medicine. Traditionally, cancer patients undergo a one-size-fits- all treatment regimen, which often leads to varied responses and significant adverse effects. Theranostics changes this paradigm by utilising molecular imaging to target cancer cells with a high specificity. This approach results in a more effective treatment process, potentially leading to higher remission rates and improved patient outcomes.

A significant breakthrough in theranostics is the FDA approval of Lutetium¹⁷⁷ (Lu-¹⁷⁷) radiopharmaceuticals for clinical use in neuroendocrine tumours (NETs) and metastatic castration- resistant prostate cancer (mCRPC). Lu-¹⁷⁷ is a medium-energy β-emitter with a physical half-life of 6.73 days.  The emitted β-particles, with 78.6% abundance, have a maximum energy of 498 keV and can penetrate surrounding tissue up to 2 mm. Additionally, Lu-¹⁷⁷ also shows two additional γ-emissions of 208 (10.4%) and 112.9 (6.2%) keV, respectively.

PET-based tracers are used to image somatostatin receptor (SSTRs) avidity in NETs and prostate cancer (PC), enabling precise targeting and treatment optimisation. NETs are a diverse group of malignancies that often overexpress SSTRs. These tumours can be effectively visualised using somato- statin analogues (SSAs) labelled with Ga-68-DOTATATE and Ga-68-DOTATOC. Depending on the avidity and selection of SSTR, peptide receptor radionuclide therapy (PRRT) with Lu-¹⁷⁷ DOTATATE (in 2018) is administered on a cycle-based regimen.

Despite the continuously evolving treatment landscape for mCRPC, the prognosis for patients remains poor. Prostate- specific membrane antigen (PSMA) PET imaging is now well-established for evaluating the biochemical recurrence (BCR) of PC, even at low PSA levels (i.e. <1 ng/ml). PSMA-PET imaging may help in identifying patients who are likely to benefit from PSMA-targeted radioligand therapy (PSMA RLT). The FDA- approved, commercially available PSMA-PET tracers include Ga-68-PSMA-11 and the F-18-based radioligands: F-18-piflufolastat (in 2021), F-18-flotufolastat (in 2023), and F-18-PSMA-1007.⁸ Lu-¹⁷⁷-PSMA-⁶¹⁷ RLT (in 2022) have received FDA approval for clinical use in therapy of mCRPC, according to specific selection criteria. Additionally, Lu-¹⁷⁷-PSMA-I&T is currently being evaluated in ongoing phase 3 trials.⁹

In addition to SSAs and PSMA analogues, fibroblast activation protein (FAP) analogues have also garnered attention as theranostics’ radiopharmaceuticals. Recently, FAPI-46 has been successfully radiolabelled with Lu-¹⁷⁷ and is currently under phase I/II trials.^10,11 Beyond oncology, theranostics hold great promise to impact a variety of fields, such as in neurological disorders, for tracking disease progression to tailor therapies effectively. The future of theranostics is using antibodies labelled with diagnostic or therapeutic agents. An example is the use of trastuzumab conjugated with radioisotopes (89Zr-trastuzumab for imaging) or cytotoxic agents (177Lu-trastuzumab for therapy) for  HER2-positive  breast  cancer  in  early-phase  trials.¹²

Despite its potential, the development and implementation of theranostics face significant challenges. Regulatory hurdles, high costs, and the complexity of developing molecular imaging agents necessitate the ongoing collaboration between researchers, clinicians, regulatory bodies, and industry stakeholders. Additionally, the integration of theranostic techniques into clinical settings requires comprehensive training for healthcare professionals to manage the complex data and advanced technologies involved. In the coming years, as technology continues to advance, the barriers will diminish, paving the way for more widespread usage. Furthermore, innovations in artificial intelligence and machine learning will enhance diagnostic accuracy and treatment planning, further refining personalised medicine  approaches.

From its beginnings, as an uncertain field, nuclear medicine has evolved into a sophisticated discipline with theranostics at its forefront, offering a clear path from diagnosis to treatment and heralding  new  possibilities  for  personalised  medicine.

COMPETING  INTEREST:
The  author  declared  no  conflict  of interest.

AUTHOR’S  CONTRIBUTION:
NF: Conception, design, drafting, acquisition, analysis, and interpretation of data for the work.
The author approved the final version of the manuscript to be published.


 

REFERENCES

1. Anger HO. Use of a gamma-ray pinhole camera for in vivo studies. Nature 1952; 170(4318):200-1. doi: 10.1038/ 170200b0.
2. Hutton BF. The origins of SPECT and SPECT/CT. Eur J Nucl Med Mol Imaging 2013; 41(1):3-16. doi: 10.1007/s00 259-013-2606-5.
3. Rich DA. A brief history of positron emission tomography. J Nucl Med Technol 1997; 25(1):4-11.
4. Townsend DW. Combined PET/CT: The historical pers-pective. Semin Ultrasound CT MR 2008; 29(4):232-5. doi: 10.1053/j.sult.2008.05.006.
5. Kalender WA. Computed Tomography: Fundamentals, System Technology, Image Quality, Applications. 3^rd ed, Publicis, Erlangen; 2011.
6. Wang C, Wang C, Zhang J, Ding M, Ge Y, He X. Develop-ment and validation of a radiogenomics prognostic model integrating PET/CT radiomics and glucose metabolism-related gene signatures for non-small cell lung cancer. Eur J Nucl Med Mol Imaging 2025. doi: 10.1007/s00259-025- 07354-4.
7. Levine R, Krenning EP. Clinical history of the theranostic radionuclide approach to neuroendocrine tumours and other types of cancer: Historical review based on an interview of Eric P. Krenning by Rachel Levine. J Nucl Med 2017; 58(Suppl 2):3S-9S. doi: 10.2967/jnumed.116.18 6502.
8. Kuo PH, Calais J, Crosby M. PSMA PET imaging in the management of patients with metastatic castration resistant prostate cancer treated with radioligand therapy. Targeted Oncol 2025. doi: 10.1007/s11523-025-01151-7.
9. Kratochwil C, Fendler WP, Eiber M, Hofman MS, Emmett L, Calais J, et al. Joint EANM/SNMMI procedure guideline for the use of 177Lu‑labeled PSMA‑targeted radioligand‑therapy (177Lu‑PSMA‑RLT). Eur J Nucl Med Mol Imaging 2023; 50(9):2830-45. doi: 10.1007/s00259-023-06255-8.
10. Eryilmaz K, Kilbas B. Fully-automated synthesis of (177)Lu labelled FAPI derivatives on the module modular lab-Eazy. EJNMMI Radiopharm Chem 2021; 6(1):16. doi: 10.1186/ s411 81-021-00130-3.
11. Cankaya A, Balzer M, Amthauer H, Brenner W, Spreckel-meyer S. Optimization of 177Lu‑labelling of DOTA‑TOC, PSMA‑I&T and FAPI‑46 for clinical application. EJNMMI Radiopharm Chem 2023; 8(1):10. doi: 10.1186/s41181- 023-00196-1.
12. Barca C, Griessinger CM, Faust A, Depke D, Essler M, Windhorst AD, et al. Expanding theranostic radiopharma-ceuticals for tumor diagnosis and therapy. Pharmaceuticals (Basel) 2021; 15(1):13. doi: 10.3390/ph15010013.