Elsevier

Seminars in Nuclear Medicine

Volume 49, Issue 5, September 2019, Pages 339-356
Seminars in Nuclear Medicine

Design and Challenges of Radiopharmaceuticals

https://doi.org/10.1053/j.semnuclmed.2019.07.001Get rights and content

This review describes general concepts with regard to radiopharmaceuticals for diagnostic or therapeutic applications that help to understand the specific challenges encountered during the design, (radio)synthesis, in vitro and in vivo evaluation and clinical translation of novel radiopharmaceuticals. The design of a radiopharmaceutical requires upfront decisions with regard to combining a suitable vector molecule with an appropriate radionuclide, considering the type and location of the molecular target, the desired application, and the time constraints imposed by the relatively short half-life of radionuclides. Well-designed in vitro and in vivo experiments allow nonclinical validation of radiotracers. Ultimately, in combination with a limited toxicology package, the radiotracer becomes a radiopharmaceutical for clinical evaluation, produced in compliance with regulatory requirements for medicines for intravenous (IV) injection.

Section snippets

Radiopharmaceutical: General Concept

As the name suggests, a radiopharmaceutical is both a pharmaceutical and radioactive. The radioactive label is used either diagnostically as an emitter of electromagnetic radiation (gamma or X-rays), of which detection allows to quantify the concentration of the radiopharmaceutical. Alternatively, the radiolabel can be used for therapeutic applications where the ionizing radiation emitted upon decay of the radionuclide is used to destroy cells. The in vivo distribution of the radionuclide in

Basic Requirements

When a tracer is administered, the general pharmacokinetic principles of distribution, metabolism, and excretion apply.87 Most radiopharmaceuticals are administered intravenously and thus absorption can be neglected.

The radiopharmaceutical will be distributed over the body with the bloodstream and accumulate in the target tissue as a result of the specific interaction of the vector with its target. At the same time the radiopharmaceutical will be cleared from plasma so that the

Production

The production of a radiopharmaceutical consists of (a) production of the radionuclide (b) incorporation of the radionuclide in the radiopharmaceutical and (c) purification and reformulation (Fig. 7). For diagnostic radiopharmaceuticals, the production time should be as short as possible to avoid loss of activity due to decay during the production process.

Radionuclides are generally obtained from a nuclear reactor (generally β emitters for radionuclide therapy), a cyclotron (generally β+

References (149)

  • A.M. Wu

    Engineered antibodies for molecular imaging of cancer

    Methods

    (2014)
  • C.J. Mathias et al.

    A convenient route to [68Ga]Ga-MAA for use as a particulate PET perfusion tracer

    Appl Radiat Isot

    (2008)
  • S.Y. Wu et al.

    Preclinical characterization of 18F-MAA, a novel PET surrogate of 99mTc-MAA

    Nucl Med Biol

    (2012)
  • E.V. Garcia

    Physical attributes, limitations, and future potential for PET and SPECT

    J Nucl Cardiol

    (2012)
  • K. Serdons et al.

    Developing new molecular imaging probes for PET

    Methods

    (2009)
  • F. Lacoeuille et al.

    Targeted alpha and beta radiotherapy: An overview of radiopharmaceutical and clinical aspects

    Med Nucl

    (2018)
  • P. Uhl et al.

    Radionuclides in drug development

    Drug Discov Today

    (2015)
  • Y. Zhang et al.

    PET imaging for receptor occupancy: Meditations on calculation and simplification

    J Biomed Res

    (2012)
  • V.W. Pike

    PET radiotracers: Crossing the blood-brain barrier and surviving metabolism

    Trends Pharmacol Sci

    (2009)
  • P.G. Stanton

    Regulation of the blood-testis barrier

    Semin Cell Dev Biol

    (2016)
  • C.C. Wagner et al.

    Approaches using molecular imaging technology – Use of PET in clinical microdose studies

    Adv Drug Deliv Rev

    (2011)
  • S.Z. Lever et al.

    Tactics for preclinical validation of receptor-binding radiotracers

    Nucl Med Biol

    (2017)
  • H.H. Coenen et al.

    Consensus nomenclature rules for radiopharmaceutical chemistry — Setting the record straight

    Nucl Med Biol

    (2017)
  • I. Velikyan et al.

    In vivo binding of [68Ga]-DOTATOC to somatostatin receptors in neuroendocrine tumours – Impact of peptide mass

    Nucl Med Biol

    (2010)
  • A. Lammertsma

    Forward to the past: The case for quantitative PET imaging

    J Nucl Med

    (2017)
  • R.A. Valdés Olmos et al.

    The GOSTT concept and hybrid mixed/virtual/augmented reality environment radioguided surgery

    Q J Nucl Med Mol Imaging

    (2014)
  • D. Casara et al.

    Optimized procedure of real-time systemic leakage monitoring during isolated limb perfusion using a hand-held gamma probe and 99mTc-HSA

    Nucl Med Commun

    (2004)
  • F. Fiz et al.

    Prevention of systemic toxicity in hyperthermic isolated lung perfusion using radioisotopic leakage monitoring

    Int J Hyperth Inform

    (2018)
  • H. Pottel et al.

    Measuring glomerular filtration rate using 51Cr-EDTA: Body surface area normalization before or after Bröchner-Mortensen correction?

    Nucl Med Commun

    (2014)
  • M. Rask-Andersen et al.

    The druggable genome: Evaluation of drug targets in clinical trials suggests major shifts in molecular class and indication

    Annu Rev Pharmacol Toxicol

    (2013)
  • D. Probst et al.

    Exploring DrugBank in virtual reality chemical space

    J Chem Inf Model

    (2018)
  • K. Van Laere et al.

    et al: Dopamine transporter SPECT using fast kinetic ligands: 123I-FP- β-CIT versus 99mTc-TRODAT-1

    Eur J Nucl Med Mol Imaging

    (2004)
  • M.S. Jakobson et al.

    Dopamine transporter imaging with [18F]FE-PE2I PET and [123I]FP-CIT SPECT—A clinical comparison

    EJNMMI Res

    (2018)
  • G.E. Smith et al.

    Inorganic approaches for radiolabelling biomolecules with fluorine-18 for imaging with positron emission tomography

    Dalt Trans

    (2011)
  • F. Cleeren et al.

    Direct fluorine-18 labeling of heat-sensitive biomolecules for positron emission tomography imaging using the Al 18 F-RESCA method

    Nat Protoc

    (2018)
  • P. Adumeau et al.

    Site-specifically labeled immunoconjugates for molecular imaging—Part 1: Cysteine residues and glycans

    Mol Imaging Biol

    (2016)
  • E.W. Price et al.

    Matching chelators to radiometals for radiopharmaceuticals

    Chem Soc Rev

    (2014)
  • L.O. Tchouate Gainkam et al.

    Localization, mechanism and reduction of renal retention of technetium-99m labeled epidermal growth factor receptor-specific nanobody in mice

    Contrast Media Mol Imaging

    (2011)
  • J. Strand et al.

    Site-specific radioiodination of HER2-targeting affibody molecules using 4-iodophenethylmaleimide decreases renal uptake of radioactivity

    Chem Open

    (2015)
  • B. Gok et al.

    Radionuclide shunt patency study for suspected ventricular-atrial shunt malfunction

    Clin Nucl Med

    (2013)
  • Y. Wong et al.

    Efficacy of yttrium-90 synovectomy across a spectrum of arthropathies in an era of improved disease modifying drugs and treatment protocols

    Int J Rheum Dis

    (2014)
  • R.F. Uren et al.

    Imaging sentinel lymph nodes

    Cancer J

    (2015)
  • ...
  • B.Y. Brewington et al.

    Brachytherapy for patients with uveal melanoma: Historical perspectives and future treatment directions

    Clin Ophthalmol

    (2018)
  • S. Wang et al.

    United States Food and Drug Administration's 510(k) pathway: Drawing implications from the approvals of brachytherapy devices

    Cureus

    (2019)
  • ...
  • ...
  • E. Dolgin

    Radioactive drugs emerge from the shadows to storm the market

    Nat Biotechnol

    (2018)
  • J.E. Blecha et al.

    An updated synthesis of [11C]Carfentanil for positron emission tomography (PET) imaging of the μ-opioid receptor

    J Label Compd Radiopharm

    (2017)
  • P.M. Rusjan et al.

    Mapping human brain fatty acid amide hydrolase activity with PET

    J Cereb Blood Flow Metab

    (2013)
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