TECHNOLOGIES

DRUG DISCOVERY

TODAY

The enabling technologies needed forPET-based molecular imaging tosupport drug developmentTerry JonesUniversity of Manchester Wolfson Molecular Imaging Centre, Christie Hospital, 27 Palatine Road, Manchester, UK M20 3LJ

Drug Discovery Today: Technologies Vol. 2, No. 4 2005

Editors-in-Chief

Kelvin Lam – Pfizer, Inc., USA

Henk Timmerman – Vrije Universiteit, The Netherlands

Imaging technologies

E-mail address: T. Jones (terry.jones@manchester.ac.uk)

1740-6749/$ � 2005 Elsevier Ltd. All rights reserved. DOI: 10.1016/j.ddtec.2005.11.010

Section Editor:Adriaan A. Lammertsma – Department of Nuclear Medicineand PET Research, Vrije Universiteit Amsterdam, TheNetherlands

It is commonly believed that all that is required to

effect PET based molecular imaging to support drug

development is a cyclotron and a PET scanner. This

review itemises the many additional technologies

needed to enable the full exploitation of PET for phar-

macodynamic and pharmacokinetic measurements of

normal and diseased tissues. There are ongoing devel-

opments in each area which when integrated add up to

significant advances in the quality and value of the

resulting data.

Introduction

It is widely understood that the technology of positron

emission tomography (PET) offers a means to support drug

development by providing pharmacokinetic and pharmaco-

dynamic data on diseased and normal tissue. Several large

pharmaceutical companies are committing significant

resources to this involving, in some cases, ownership of their

own facilities as well as collaborations with external clinical

academic PET groups. However, little has been written on

how encompassing is the infrastructure of this technology

and how the sum of its components provides for the overall

quality of the data within the imaging science of PET [1]. It

follows that improvement in each of the individual techno-

logical componentsmakes for appreciable gains in the overall

efficiency and quality of complex experimental medicine

studies within the exacting conditions for clinical and

research governance in the modern era. To help illustrate

this, this review discusses the recent experience of establish-

ing what is one of the first PET-based molecular imaging

centres specifically built and set up to encompass all the

technologies needed to undertake research in oncology

and brain disorders. Having to decide on the installation of

state-of-the-art equipment within a projection for the

expected increased growth in this unique investigative area,

focuses the mind as to what technologies need to be given

consideration. The message is that for those wishing to

establish or indeed appreciate access they might have to such

a centre, there are areas of continuing technological growth.

The overall financial commitment is significant as is the need

for extensive, detailed planning in the integration of these

technologies and the associated documentation of equip-

ment and procedural quality control. This review system-

atically covers the individual enabling technologies to affect

the use of PET to support drug development.

The cyclotron

A cyclotron is needed as a source of short-lived positron

emitting radioisotopes. There was amystic for operating such

an accelerator in a clinical research environment. However,

commercial cyclotrons are now available from several estab-

lished companies and have good reliability and operational

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Drug Discovery Today: Technologies | Imaging technologies Vol. 2, No. 4 2005

records. Of note is the growth of distribution centres for

fluorine-18 labelled compounds which, with its 110 min

radioactive half-life, means for those only interested in this

tracer, receiving it from a commercial supplier is muchmore

attractive than operating ones own cyclotron. This places

the justification for the ownership of such equipment on the

production and application of the short-lived isotopes of

carbon-11, nitrogen-13 and oxygen-15 which have radio-

active half-lives of 20.1, 10 and 2.1 min, respectively. The

technology ofmodern cyclotrons is such thatmore than one

radioisotope can be produced at any given time. A commer-

cial cyclotron is fitted with chambers that hold target mate-

rial during irradiation by the cyclotron. This technology is

fairly mature and there has been little innovation in this

area in recent years. However, some research groups con-

tinue to strive to improve the design of cyclotron targets

with the aim of increasing the radioistopic yield and mini-

mising the amount of carbon-12 present which affects

the purity (specific activity) of the molecule labelled with

carbon-11.

Supply of radioactivity from the cyclotron

The cyclotron needs to be treated as a reagent bottle for the

short-lived isotopes which have to be distributed efficiently,

flexibly and safely to the shielded enclosures where either

experimental radiochemistry or radiosyntheses of molecules

for human administration is carried out. The challenge is to

automate this process to meet these requirements and yet

commercial equipment to accomplish this is not available.

Hence each centre needs to implement its own design of

facility as to its own projected needs. The range of precursor-

labelled molecules that are possible means that many dis-

tribution options need to be available. As higher quality of

the radiolabelled precursor is sought, consideration is being

given to be able to monitor on-line the purity, for example,

specific activity of these precursors to maintain quality con-

trol as well as to assess new technologies being developed to

improve on this quality. Attention to improving specific

activity has implications with respect to maximising the

opportunity for micro-dosing studies which are becoming

increasingly attractive for first into-man studies while mini-

mising toxicology issues. It is also important when using

potent agonists as radioligands as well as the challenge of

using ligand studies for small animal PET where cold tracer

levels have a pharmacological affect evenwith small amounts

of radiolabelled ligand used for such studies.

Hot cell-automated radiosynthesis and GMP

production

There are a small number of companies specialised in hot cell

production for PET probes and importantly some have

entered into consortia with companies specialised in clean

room technology with the aim of encompassing this with hot

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cell technology to the highest cGMP standards. The main

implications for this is the challenge of operating such com-

posite technologies which need special services both for

supplying the hot cells and safely exhausting their environ-

ment and that their establishment and operation is both

expensive and space-consuming.

There is relatively little choice in the commercially avail-

able automated ‘rigs’ for remote hot cell-based chemistry

and they are expensive. While providing immediate solu-

tions there is scope for developing more basic, lower cost

systems based upon loop and solid-phase chemistry; at the

same time microreactor or fluidic chemistry continues to

attract developments with reaction times of a few seconds

being reported. A major consideration is the quality of the

clean room environment in which the radiolabelled tracers

of ligands are synthesised and dispensed before adminis-

tration into patients. Clearly, the health risk associated with

a product that is made for a specific patient and adminis-

tered within 30 min or so following manufacture is low

compared to a batch produced pharmaceutically to be used

for many patients within an expiry time of months. Never-

theless, modern legislation is falling on the side of caution

and standards are increasing for the production of chemi-

cals being administered to humans. Hence, when designing

and investing in a hot cell laboratory for such purposes, it is

clearly prudent to aim for a standard higher than the

previous one given that legislation has in general become

increasingly stringent. In addition, collaborations between

academia and the pharmaceutical industry, where the high-

est standards are adhered to, will naturally steer upwards

the quality of the laboratory and the practise therein for

manufacturing labelled compounds. As a result, running

costs for such facilities become significantly higher than in

former practice. Recent deliberations undertaken by the

FDA for such operations have produced recommendations

that attempt to soften the impact of having to adhere to the

highest safe standards. However, it is a brave individual

responsibility for a major new initiative in PET-based mole-

cular imaging which will not err on the safe, higher end of

quality. This especially is the case given that it might

become a weak component in the future within the whole

investment and one that is not easily rectified given the

engineering and space demands for maintaining clean

room GMP facilities.

Quality control of radiolabelled compounds for human

use

The challenge of providing quality control of the chemical

and radiochemical purity of a compound that is labelled with

20.1 min half-life carbon-11 before its administration to a

human being is demanding, especially when the compound

is within a family of potent substances. The highest standards

are mandatory and consideration is being given to the ability

Vol. 2, No. 4 2005 Drug Discovery Today: Technologies | Imaging technologies

to characterise the chemical form of the tracer or ligand over

and above its position as a peak on a high-pressure liquid

chromatography (HPLC) column. The development of such

assays will continue along with rapid pyrogenicity testing

where recent technology provides results within 10 min. The

net result will produce products that not only are of the

highest safety standards but will also directly impact on

the quality of the resulting PET data and in turn optimise

the cost-effectiveness of such expensive investigations.

Environmental monitoring and discharge of

short-lived radioactivity

Staff will need the presence of environmental radiation mon-

itoring to detect accidental room release of radioactivity.

Increasingly high standards are required to measure the

inevitable amounts of small levels as well as the accidental

discharge of radioactive gaseous materials especially for

facilities located within hospitals and built up urban areas.

Highly sensitive discharge monitoring has been developed

for this purpose and can prove most effective in identifying

leaking apparatus where previously not possible. Such

detection has direct implications for improving the quality

control of manufactured products. The cost for implement-

ing comprehensive radiationmonitoring in a large PET centre

can amount to some 20% of the cost of a PET scanner or

cyclotron.

Direct delivery of short-lived radioisotopes to humans

being PET scanned

This includes radioactive gases which are either inhaled

directly by the patient or in the case of oxygen-15 when used

to measure tissue blood flow, converted into labelled water

for intravenous injection. Although the use of this delivery

system for studying regional brain activation is less prevalent

than in former times, owing to the introduction ofMRI-based

methods, measurement of myocardial perfusion and, in par-

ticular, tumour perfusion using oxygen-15 labelled water is

still considered the gold standard. In the case of oncology,

such measures are clearly important with respect to defining

the delivery of a pharmaceutical to the tumour and as a

pharmacodynamic measure of anti-angiogenesic and anti-

vascular agents. Various methods have been adopted for the

technology of administering labelled water but the recent

availability of a ‘hands off’ device which uses commercial

sterile exchangers for dissolving oxygen-15 labelled water

vapour piped from the cyclotron is an important develop-

ment (HIDEX Oy, Turku, Finland).

State-of-the-art positron emission tomographs

For pharmacokinetic and pharmacodynamic data collection

the emphasis on PET scanner performance is on realising high

sensitivity over a wide dynamic range with the highest spatial

resolution possible. The key to this has been to collect data in

the nonsepta, 3D data mode thereby capitalising on the

electronic collimation offered through coincidence count-

ing. This approach has worked well for the brain but has

proved less successful while imaging the thorax or abdomen.

This is due to the high loss photon fluxes incident on the

detectors resulting in loss of effective sensitivity owing to

detector dead time and the need to correct for the registration

of high random coincidences. In addition, the registering of

increased scattered coincidences and corrections for these

further reduces the effective sensitivity. This position has

been improved upon with the introduction of scintillation

detectors which emit more light that decays away faster than

the previous BGO crystals. An example of this the crystal LSO,

which already is proving an advance for rapid PET diagnostic

scans. However, little exploitation has beenmade of this new

technology for recording kinetic data over the abdomen or

thorax and the overall gain therein remains to be demon-

strated. Nevertheless, one is confident that this technology is

advancing and already projections are being made as to what

is known as the fifth generation of PET scanner. Here, an

overall improvement a factor of 10 in effective sensitivity at

high data recording rates is predicted within 2–3 years as

better use is made of wide angle, 3D data collection and the

difference in the time of arrival of the paired coincident rays,

using time of flight [2]. For scanners that record data over the

length of the body, machines that are combined with other

transaxial imaging devices such as X-ray, CT have made a

considerable impact and there is promise of a combined PET

andMRImachine. In the later case, the challenge is to be able

to operate scintillation counters in a high magnetic field

which will distort the performance of the traditionally used

photo multiplies that are used to collect the light emitted

from the scintillating crystal. Recent report of work substitut-

ing the photo multiplier with silicon photodiodes offers a

read out technology that could be adapted for a combined

PET/MRI imaging device [3]. Much of the value made of the

combined modalities to date has been in providing more

accurate anatomical location of lesions identified in the PET

image as well as a convenient means to correct for attenua-

tion of the PET data because of the tissue’s absorption of the

ion of the emitted gamma rays. However, manymore uses are

to be made of the combined imaging modalities including

using the accurate anatomical information to correct the PET

data from a given physical structure for loss of signal due to

the finite spatial resolution of the PET camera. In addition,

there will be an emphasis on identifying major feeding

arterial blood vessels from which input function of a tracer

to a specific organ might be measured for subsequent quan-

tification of kinetic data thereby minimising the need to

withdraw arterial blood.

Although the earlier pioneering work in PET centered on

the brain, the projected development of high resolution

cameras for brain imaging are less clear. The current high-

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Drug Discovery Today: Technologies | Imaging technologies Vol. 2, No. 4 2005

resolution research tomograph LSO-based PET camera devel-

oped by CTI, and now supported by Siemens [4], has a spatial

resolution of 2.5 mm. This is maintained across the brain

using a dual layer of detector. There is some further scope for

improvement for brain PETwhichmight be stimulated by the

prospect of new diagnostic PET procedures emerging for the

brain for example in dementia and psychotic diseases. The

advances seen in recent years in the technology for small

animal PET scanning where spatial resolutions approaching

1 mm have been achieved suggests the transfer of that tech-

nology to the design of the next generation of PET scanner

dedicated for the human brain.

Recording of the blood concentrations of tracer or

ligand during a PET scan

To derive quantitative pharmacokinetic and pharmacody-

namic data, it is necessary in many instants to record the

time course of arterial and in some cases the venous con-

centrations to provide the input function for kinetic model-

based analyses. High sensitivity on-line detectors have been

developed with the latest versions operating in the coinci-

dence mode with as high as 80% efficiency for volumes of

blood assayed for up to 500 ml. This provides for the sensi-

tivity needed to accurately follow blood concentration data

over some five radioactive half-lives of carbon-11. In parallel

with the monitoring of whole blood concentrations there is

the need to derive the partitioning of total radioactivity of

blood between the parent tracer or ligand and its radiolabeled

metabolite or metabolites. In most cases this involves rapid

HPLC where the radioactive concentrations are small. The

challenge here is to maximise the counting times for com-

ponents within the HPLC spectral output. Multiwell auto-

matic counting devices are one approach to this but higher

sensitivity spectral resolution methods are also being con-

sidered.

Reconstruction of the time course of 3D recorded

PET data

This is proving demanding as a kinetic sequence, for example,

recorded with the HRRT brain camera can result inmany giga

bytes of data. Advanced IT technology is required to rapidly

transfer the data away from the source of collection and

reconstructed off-line using computer cluster and storage

access networks the composite technology for which is

expensive and needs to be tailored for a particular research

and applications environment. For this, raw data needs to be

retrieved and processed in different ways to develop applica-

tion-specific reconstructions.

Preclinical discovery and development of new PET

tracers and ligands

The technology associated with this area could in principle

be as encompassing as drug discovery and development in

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that in addition to the imagingprobehaving tobe specific for

themolecular binding site or pathway of interest, considera-

tion needs to be given to its metabolism, passage through

endothelial barriers and nonspecific binding. Here, there is

clearly a case for capitalising on the work of the pharmaceu-

tical industry with its huge molecule generating base cover-

ingmolecular modelling, combinatorial chemistry and high

throughput screening. The case for an academic-based PET

centre investing in such technology would not be strong.

This points to the need to forge close working collaborations

with the pharmaceutical industry or indeed those industries

who themselves are establishing in house PET programmes

providing pipelines of new imaging probes that sustain and

grow the PET investigative base for experimental medicine.

The role of academic PET centres is to contribute to the

translationof pharma-based discoveredmolecules to becom-

ing useful imaging probes for pharmacodynamic and phar-

macokinetic studies in patients. To effect this translation

within an academic PET centre, there does need to be facil-

ities that extend those resident in industry with respect to

assaying the biological properties of probes labelled with

short-lived cyclotron produced radioisotopes. These include

cell and tissue culture laboratories equipped with the appro-

priate technology as well as that needed for measuring

biodistributions in laboratory animals. Small animal PET

camera technologies offer a key role in that they can be used

to undertake the scanning procedures and protocols to be

implemented in patients. This provides a means of charac-

terising, against ex vivo assays, and before human applica-

tion, the methodology including the kinetic image analysis

implemented toderive parameters such as bindingpotential,

receptor density and flux of a molecule into and through a

tissue. The additional glue to forging working relationships

with industry is that academic centres will contain the skills

to operate and exploit many of the key technology areas

driven by expertise in physics, mathematics, engineering

and computing working alongside clinician and biological

scientists. The key to this multidisciplinary activity is one

of focussing on common goals to derive original data on

the biology of human diseased tissue and to support drug

development.

There is a considerable amount of activity undertaken

within the physics and electronic engineering communities

addressing the challenge of realising high-resolution/high-

sensitivity small animal PET cameras. Spatial resolutions as

high a 1 mmhave been achieved and sensitivities of up to 4%.

However, the challenge has been to realise such resolutions

and sensitivities in the same device owing to the need to

overcome mispositioning errors that result from increasing

the depth and hence the efficiency of the detectors surround-

ing the animal.What is required are high resolution, depth of

interaction readouts of detected events in scintillating mate-

rials that have high efficiency for registering the gamma rays

Vol. 2, No. 4 2005 Drug Discovery Today: Technologies | Imaging technologies

emitted from the animal. Here, there is the potential for

increasing the sensitivities realised to date by an order of

magnitude. Such technologies differ from those used for

imaging patients. It has the potential for completely encom-

passing the whole animal thereby maximising the sensitivity

needed to realise high spatial resolution kinetic studies and

the ability to undertake ligand-binding studies within the

confines of the finite specific activities achievable for imaging

probes labelled with carbon-11 and fluorine-18. In addition,

high-sensitivity/high spatial resolution tomographs would

offer the possibility to monitor blood concentrations within

the chambers of the heart or major blood vessels such as the

aorta thereby avoiding the need to withdraw blood needed

for quantitation kinetic analysis of the tissue data. This is

particularly important in small animals because of the limits

on the amount of blood that can be with withdrawn and the

practicalities of doing this.

Administration of PET enabling technologies

As will be appreciated, the range of technologies needed for a

research orientated PET centre is diverse and continues to

evolve. In the modern era of documentation of equipment

performances, which rest on the derivation of comprehensive

standard operating procedures, it is relevant to note that in

such a centre there are approaching 120 operations. Most of

these need documentation and mechanisms for recording

procedural changes. This is something that is foreign tomany

academics and yet in the era of clinical accountability and

collaborations with industry, which is more heavily docu-

mented, a technology needs to be in place to effect and

manage this task efficiently under one quality assurance

umbrella.

Conclusions

It is commonly understood that the enabling technology

needed for PET-based molecular imaging centres on a cyclo-

tron and PET camera. As can been seen, the additional items

of technology and the accompanying expertise can repre-

sent as big an investment and contribute fundamentally to

the value and quality of the derived PET data. Within many

components of this, there is considerable scope for improv-

ing on performance which when integrated has a major

impact on the overall quality of the information derived on

the pharmacodynamics and pharmacokinetics of new ther-

apeutic agents and hence the ability to support the devel-

opment of new drugs. The extent of the technology and

the range of expertise needed to develop and exploit it

within the biological and clinical setting do offer attractive

application-oriented environments for young physical

scientists to commit their careers. To enhance this attrac-

tion, there is a need to establish more structured training

programmes which could be contributed to by consortia

of the leading PET centres containing such expertise,

http://www.manchestermolecularimaging.com/.

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