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Principles of Molecular Targeting for Radionuclide Therapy

  • Reference work entry
  • First Online:
Nuclear Oncology

Abstract

Molecular targeting requires assessing several factors that come into play such as the location of the target, the choice of radionuclide, the inertness of the bifunctional chelate and stability of the covalently bound halogens, matching the residence time in the tumor with the physical half-life of the radionuclide, the scale and scope of the disease, and the absorbed dose sensitivity of the targeted tumor compared to normal tissue. The principles of molecular targeting are well established, but a paradigm shift from designing a medium-affinity radiotracer used to determine target density to designing a high-affinity, high-target density radioligand to maximize the target-to-nontarget ratio should increase the probability of detecting lesions smaller than the instrument resolution.

Developing and validating a therapeutic radiopharmaceutical for a single target is necessary, but often not sufficient to produce a toxic event because of other mechanisms that are only partially understood. These include nontargeted effects due to radiation emitted from neighboring, targeted cells as well as bystander effects produced by the cellular processing of radiation not necessarily impinging on DNA. Both of these indirect consequences of cellular radiation could make a substantial contribution to the efficacy of targeted radionuclide therapy. These mechanisms should be exploited to optimize the efficacy of targeted radiotherapy and overcome the inefficiency of tumor control due to nonuniform distribution of radiation dose. The design approach to take advantage of the indirect consequences of cellular radiation depends heavily on further elucidation of the indirect effect. The successful combination of these two should lead to more effective nuclear radiotherapy.

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Abbreviations

18F-DOPA:

2-18F-Fluoro-l-3,4-dihydroxyphenylalanine

18F-FP-TZTP:

3-[4-[(3-[18F]fluoropropyl)thio]-1,2,5-thiadiazol-3-yl]-1,2,5,6 tetrahydro-1-methylpyridine

125IUdR:

5-[125I]Iodo-2’-deoxyuridine

ADAM:

2-[2-(Dimethylaminomethylphenylthio)]-5-[125I]iodophenylamine

ATM:

Ataxia telangiectasia mutated

ATR:

ATM and RAD3 related

ATSM:

Diacetyl-bis(N4-methylthiosemicarbazone

AUC:

Area under the time-activity curve

Br-BHPE:

Bromo-l,l-bis(4-hydroxyphenyl)phenylethylene

CBF:

Cerebral blood flow

CB-TE2A:

Cross-bridged macrocyclic chelators

CEA:

Carcinoembryonic antigen

CT:

X-ray computed tomography

DAT:

Dopamine transporter

DFO:

Desferrioxamine B

DNA:

Deoxyribonucleic acid

DOPA:

l-3,4-dihydroxyphenylalanine

DOTA:

1,4,7,10-Tetraazacyclododecane-1,4,7,10-tetraacetic acid

EMA:

European Medicines Agency

EPR:

Enhanced permeability and retention

FACS:

Fluorescence-activated cell sorting

FDA:

United States Food and Drug Administration

FWHM:

Full-width half-maximum

GFP:

Green fluorescent protein

GLUT:

Glucose transporter

Gy:

Gray unit (ionizing radiation dose in the International System of Units, corresponding to the absorption of one joule of radiation energy per kilogram of matter)

HCT116:

Cell line of human colon carcinoma

HER:

Human epidermal growth factor receptor

IdU:

Iododeoxyuridine

INXT:

(R)-N-methyl-(2-[125I]iodo-phenoxy)-3-phenylpropylamine

IQNB:

3-R-Quinuclidinyl 4-S-[123I]iodobenzilate

IUdR:

Iododeoxyuridine

IV:

Intravenous

IVME2:

Iodovinyl-11-beta-methoxyestradiol

LET:

Linear energy transfer

LNCaP:

Lymph node metastasis from carcinoma of the prostate

LS174T:

Colon adenocarcinoma cells line name

MABG:

Meta-[211At]astatobenzylguanidine

mAbs:

Monoclonal antibodies

mAChR:

Muscarinic acetylcholine receptor

MBF:

Myocardial blood flow

MCF-7:

Michigan Cancer Foundation-7, a breast cancer cell line

MIBG:

Meta-iodobenzylguanidine

MIP:

Molecular Insight Pharmaceuticals

mRNA:

Messenger ribonucleic acid

NET:

Norepinephrine transporter

NHL:

Non-Hodgkin’s lymphoma

NET:

Norepinephrine transporter

p-SCN-BN-CB-TE2A:

11-bis(carboxymethyl)-1,4,8,11 tetraazabicyclo[6.6.2]hexadecane

p-SCN-BN-DOTA:

S-2-(4-Isothiocyanatobenzyl)-1,4,7,10-tetraazacyclododecane tetraacetic acid

PCa:

Prostate cancer

PCB-TE2A:

Cross-bridged (propyl) TE2A

PET:

Positron emission tomography

PMPA:

2-Phosphonomethylpentanedioic acid

PSMA:

Prostate-specific membrane antigen

RAD3:

A 5′ to 3′ DNA helicase involved in nucleotide excision repair and transcription (from “RADiation sensitive”)

RIBBE:

Radiation-induced biological bystander effects

RNA:

Ribonucleic acid

ROS:

Reactive oxygen species

SERT:

Serotonin transporter

SOD:

Superoxide dismutase

SPECT:

Single-photon emission computed tomography

SPECT/CT:

Single-photon emission computed tomography/computed tomography

SUV:

Standardized uptake value

T/B:

Target-to-background

T/NT:

Target-to-nontarget

TE2A:

1,8-N,N′-bis-(carboxymethyl)-1,4,8,11-tetraazacyclotetradecane

TETA:

1,4,8,11-Tetraazacyclododecane-1,4,8,11-tetraacetic acid

TMS:

Transfectant mosaic spheroids

TMX:

Transfectant mosaic xenograft

TOC:

Therapy operating characteristic

TRODAT:

Technetium, 2-[[2-[[[3-(4-chlorophenyl)-8-methyl-8-azabicyclo[3.2.1]oct-2-yl]methyl](2-mercaptoethyl) amino]ethyl]amino]ethanethiolato(3-)-oxo-[1R-(exo-exo)]

Zr-DFO:

Zirconium desferrioxamine B

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Authors and Affiliations

  1. Molecular Tracer, Bethesda, MD, 20814, USA

    William C. Eckelman

  2. Strathclyde Institute of Pharmacy and Biomedical Sciences, Strathclyde University, 161 Cathedral St, G4 0RE, Glasgow, UK

    Marie Boyd

  3. Institute of Cancer Sciences, University of Glasgow, Garscube Estate, Switchback Road, G61 1QH, Glasgow, UK

    Robert J. Mairs

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  3. Robert J. Mairs
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  1. Molecular Imaging and Therapy Service, Memorial Sloan Kettering Cancer Center, New York, New York, USA

    H. William Strauss

  2. University of Pisa, Regional Center of Nuclear Medicine, Pisa, Italy

    Giuliano Mariani

  3. University of Pisa, Regional Center of Nuclear Medicine, Pisa, Italy

    Duccio Volterrani

  4. Molecular Imaging and Therapy Service, Memorial Sloan Kettering Cancer Center, New York, New York, USA

    Steven M. Larson

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Eckelman, W.C., Boyd, M., Mairs, R.J. (2017). Principles of Molecular Targeting for Radionuclide Therapy. In: Strauss, H., Mariani, G., Volterrani, D., Larson, S. (eds) Nuclear Oncology. Springer, Cham. https://doi.org/10.1007/978-3-319-26236-9_32

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