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Imaging Platforms and Drug Development: An Introduction

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Pharmaco-Imaging in Drug and Biologics Development

Part of the book series: AAPS Advances in the Pharmaceutical Sciences Series ((AAPS,volume 8))

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Abstract

Medical imaging over the last century contributed significantly in the knowledge of disease, disease mechanisms, and even in the molecular manipulation of disease with drugs and biologics. The discovery of how molecular biomarkers express, locate, change, and often drive physiologic processes has been greatly expanded using imaging. The advances in medicine from imaging have driven even more development of imaging platforms toward miniaturization for use in the nonclinical laboratory. The recent additions in the area of optical imaging with self-illuminating quantum dots (QDs), the advances in the libraries of knockout/in animal models, chemical analytical methods now applied to imaging (MALDI and SIMS-MS and MRS imaging) have made small regional in vivo sampling possible. The drug development paradigm is now shifting from the formalism of the pharmacology and toxicology paths of the last century that has served us well to a potentially revolutionary path which will reduce animal usage and obtain time rate of change of biomarker and physiologic responses to drugs and interventional strategies. This chapter is intended to be a broad overview of imaging platforms for the readers to introduce themselves into this subject matter and to come away with a new knowledge of these technologies and how they may assist in the advanced development of drug or biologics and toward regulatory approval.

Mr. Moyer is currently contracted to the Biomedical Advanced Research and Development Authority (BARDA), Health and Human Services (HHS), Washington, DC as Sr. Science Advisor, Project BioShield, Chemical, Radiologic and Nuclear Threats (CRN Group, through Tunnell Government Services (TGS), Bethesda, MD; He owns and operates his consulting firm, BRMoyer & Associates, LLC, out of Bedford, NH, specializing in imaging systems and approaches for drug development, radiation and chemical injury medical countermeasures, and pharmacokinetics and toxicokinetics of drugs and biologics.

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Notes

  1. 1.

    RECIST: Response Evaluation Criteria in Solid Tumors (Therasse 2002).

  2. 2.

    http://www.bioclinica.com/blog/evolution-ct-scan-clinical-trials, The Evolution of CT Scan Clinical Trials, Stuart Jackson blog on July 22, 2011.

  3. 3.

    The Hounsfield unit (HU) scale is a measure of the attenuation coefficients within an object in which the radiodensity of distilled water at standard pressure and temperature (STP) is defined as zero HU and the radiodensity of air at STP is defined as −1,000 HU. Muscle and bone will measure as HU exceeding 30 and 300 HU, on average, respectively.

  4. 4.

    A Doctor’s Guide to Nuclear Medicine, Barry E Chatterton, Sr. Dir., Nuclear Medicine, Royal Adelaide Hospital; http://www.rah.sa.gov.au/nucmed/nucmed/ncmd_docguide.htm .

  5. 5.

    β-CFT, is a cocaine-derived drug used in dopamine stimulation scientific research. CFT is a phenyltropane-based dopamine reuptake inhibitor.

  6. 6.

    ASNC IMAGING GUIDELINES FOR NUCLEAR CARDIOLOGY PROCEDURES, Stress protocols and tracers Milena J. Henzlova MJ, Cerqueira MD, Hansen CL, Taillefer R, Siu-Sun Yao S-S, http://www.asnc.org/imageuploads/ImagingGuidelinesStressProtocols021109.pdf and, ASNC IMAGING GUIDELINES FOR NUCLEAR CARDIOLOGY PROCEDURES Single Photon-Emission Computed Tomography, Thomas A. Holly TA, Abbott BG, Al-Mallah M, Calnon DA, Cohen MC, DiFilippo FP, Ficaro EP, Freeman MR, Hendel RC, Jain D, Leonard SM, Nichols KJ, Polk DM, Soman P, http://www.asnc.org/imageuploads/ImagingGuidelineSPECTJune2010.pdf.

  7. 7.

    Animation of gated F-18 FDG cardiac PET images (from the Univ. of Kansas Medical School, Nuclear Medicine Dept.: http://www.rad.kumc.edu/nucmed//clinical/pet_gated_fdg.htm and http://www.rad.kumc.edu/nucmed/clinical/PET_gated_FDG_3v_animated.htm.

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    Brian R. Moyer

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    Tom C.-C. Hu

Appendix 1. Selected Biomarkers and Interventional Probes Useful in Imaginga

Appendix 1. Selected Biomarkers and Interventional Probes Useful in Imaginga

Biomarkers/imaging targets (used in drug development)

Tracer or probe

Imaging modality

Suggested citations (see the full ref. listing)

Sugar and lipid metabolism:

F-18 FDG

PET

Phelps; Valk; Huang,

 Cancer chemo/radiation therapy

–

MR T2

 Cardiac metabolism

F-18 FDG

C-11palmitate;C-11-choline

PET

PET

 Brain metabolism/flow

 Lung cancer (SSTR+)

N-13 ammonia/Rb-82

Tc-99m Depreotide

PET

 Pancreatic cancer

Ga-68 DOTA-NOC or

SPECT

 Brain chemistry

F-18 DOPA

PET

 HDL and LDL metabolism

Tc-99m HDL and LDL

SPECT

 Free fatty oxidation rates

C-11 acetate

PET

Blood flow (vascular):

 

PET

 BOLD signal–oxygenated Hgb

 

fMR (@ 3Tb)

Ferris

 Cardiac and brain perfusion

Rb-82, O-15 H2O; N-13 ammonia

PET

SPECT

 Vascularobstruction/aneurysms

Tc-99m ECD *Neurolite®

 

 Blood cells or labeled albumin

Gd contrast; Fenanoparticles

In-111 oxine; Tc-99m HMPAO

MR

SPECT

 Apoptosis

Tc-99m Annexin V

 

Schlaug

 Stroke/hypoxia

ADC change

MR

Krohn, Corbett; Dugas

Elastase-induced emphysema

Hyperpolarized Helium-3

MR

Cardiac:

 Glucose metabolism

F-18 FDG

PET

Phelps

 Perfusion

Rb-82, O-15 H2O; N-13 ammonia

PET

 

 Fatty acid metabolism

I-123 BMIPP; I-124

SPECT; PET

 

 Cationic pumps

Tc-99m—Sestamibi

SPECT

Machac

Tc-99m Tetrofosmin

SPECT

Machac

Tc-99m furifosmin (Q12)

SPECT

 

Tl-201

SPECT

Machac

 Acetylcholinesterase

C-11 Edrophonium

C-11 Pyridostigmine

PET

 

DNA synthesis

F-18 FLT

C-11 FMAU

Br-76 BFU

PET

Lu

Inflammation/infection:

 Neutrophil elastase

Apatamer interference

SPECT

Charlton

 White blood cells

In-111-oxine

SPECT

Sinha

 Neuroinflammation

 

SPECT/PET

Deyton

 HIV

 

PET

Esposito

 Cell labeling

Various. Incl BLI.QD

SPECT/PET/BLI

 

 Generalized/focal infections

FDG/FLT

PET

Van Waarde

Muscarinic receptor:

 M2

F-18 FP TZTP

PET

Eckelman

Dopamine transporters

C-11 Cocaine

PET

Eckelman

Dopaminergic/Serotonin:

 D2 receptor

O-15 U91356a

C-11 Raclopride

C-11 β-CFT

C-11 β-CIT

C-11 β-CNT

PET

Eckelman

Dopamine metabolism:

 D1 receptor

O-15 SKF82958

PET

Eckelman

Benzodiazepine receptor

O-15 Lorazepam

PET

Eckelman

NMDA receptor (dopamine release)

C-11 Raclopride

PET

Eckelman

5-HT1A receptor

C-11 NMSP

PET

Eckelman

F-18 FCWAYS

 

Eckelman

5-HT2A receptor

F-18 Setoperone

PET

Eckelman

Neurologic disease:

 

PET

Klunk

 Alzheimer’s disease (AD)

F-18 FDG; C-11 PIB;

 

Sossi

 Aβ-amyloid

AMYViD; F-18

FDDNP; Fe accumulation

PET, MR T2

Esposito

 Neuroinflammation

C-11 Arachidonic acid

MR

 

ADC change (with contrast)

 Glioma

F-18 FDG

PET

 Pheochemocytoma

I-123/I-124 MIBG

SPECT/PET

 Multiple sclerosis

ADC changes

MR

Bone:

 

 Density/metastases

NaF (F-18); F-18-FLT

CT; PET

 Marrow cellularity

In-111 HPAMO WBCs

SPECT

Diffusion weighted MR

MR

F-18 FDG. F-18-FLT

PET

Cancer and Tumor Hypoxia:

 Hypoxia

F-18 FMISO

PET

Krohn

Other nitroimidazoles: FAZA, FETA, FETNIM, EF3, EF5, IAZA; Cu-64-ATSM

 

O2-sensitive MR contrast BOLD agents:

MR

 Perfluorotributylamine,

 Hexafluorobenzene,

 Hexomethyldisiloxane,

 Trifluoroethoxy-MISO

Lactate MRS as a consequence of hypoxia:

MRI, NIR, BLI

 O2-line width sensitivity

ESR

 Glioblastomas

F-18 FDG

PET

I-123/I-124 MIBG

PET

 Prostate

I-123-MIP-1095

SPECT

 Pheochromocytoma

C-11 Me-CGS 27023A

PET

 Matrix metalloproteinases

C-11 Me-halo-CGS 27023A

PET and BLI

C-11 Biphenylsulfonamide

PET

 Luciferase-PET probes (for mice)

C-11 d-luciferin methyl ester

PET/BLI

C-11 d-luciferin methyl ether

PET/BLI

Renal function:

 

 Renal stones

contrast

CT; MR

 Renal flow

Tc-99m inulin

SPECT

 Tubular secretion

In-111 DTPA

SPECT

Bowel function:

   

 Obstruction/torsion/transit time

X-ray (with contrast), CT

CT, US

 Appendicitis

In-111 WBCs, peptides

SPECT, PET, CT, US, MR

 Diffusion-weighted MR

DW-MR

 

Hepatic function:

 Biliary flow

Tc-99m HYNIC-GC

SPECT

 

Genitourinary function/cancers:

 Cervical cancer

Cu-64 DOTA-Cetuximab

PET

Anderson

 Prostate cancer

Lung function/cancers:

 

 Fibrosis

(ROI scoring; HU measures)

CT

 Ventilation

Xe-133, Tc-99m MAA

SPECT

 SSTR + lung cancer

Cu-64-TETA-octrotide

PET

Vascular disease and function :

 LDL

Gd-DTPA-SA-LDL

MR

 

 DVT (deep vein thrombosis) and pulmonary embolism

Tc-99m IIbIIIa receptor antagonists

SPECT

 Aneurysms

Gd-MS-325/vascular contrast

MR

 Angiography/Venography

X-ray contrast

CT

Taillefer; Bates

 GI flow/distortions

Microbubbles

US

  1. Abbreviations: NIR near infrared, BLI bioluminescent imaging, ESR electron spin resonance, OI and QD optical and quantum dot, PET positron emission tomography, SPECT single photon emission computed tomography, CT computed tomography, Planar single projection nuclear image, US ultrasound, MR magnetic resonance, fMR functional MR using the BOLD (blood oxygen level dependent)
  2. aThe listing is not meant to be exhaustive and does not intentionally exclude other innovative probes
  3. b3T: 3 Tesla (3T) magnetic field strength required

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Moyer, B.R. (2014). Imaging Platforms and Drug Development: An Introduction. In: Moyer, B., Cheruvu, N., Hu, TC. (eds) Pharmaco-Imaging in Drug and Biologics Development. AAPS Advances in the Pharmaceutical Sciences Series, vol 8. Springer, New York, NY. https://doi.org/10.1007/978-1-4614-8247-5_1

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