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British Journal of Radiology (2003) 76, S50-S59
© 2003 British Institute of Radiology
doi: 10.1259/bjr/30399077
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Full Paper

Positron emission tomographic imaging of angiogenesis and vascular function

G R Laking, MBChB, BMedSci1 and P M Price, MA, MD, FRCR2

1 Cancer Research UK PET Oncology Group, Hammersmith Hospital, Du Cane Road, London W12 0NN and 2 Academic Department of Radiation Oncology, Christie Hospital, Wilmslow Road, Manchester M20 4BX, UK


   Abstract
Top
 Abstract
Introduction
 PET imaging
 Perfusion imaging with tracers
 PET perfusion imaging with...
 PET tracer imaging of...
 Tracers for molecular imaging...
 Summary and conclusions
 References
 
Surrogate markers of clinical outcome are important in anticancer drug research, since clinical criteria of response develop only slowly and may be confounded by other processes than drug effect. The need for surrogate outcome markers is especially great with newer agents that may act by tumour stabilization as opposed to shrinkage. Neoplastic angiogenesis is associated with a number of detectable changes at molecular and microcirculatory levels. Therefore, direct study of angiogenic molecular biology and tumour circulation before during and after treatment may offer useful surrogate markers for vascular-targeted therapies. The main advantage of radiotracer imaging with positron emission tomography (PET) is its functional specificity. This article will review two main areas: (a) the methodology behind PET imaging of tumour blood supply with 15O-oxygen labelled compounds; and (b) newer tracers in development as markers of angiogenetic biology.


   Introduction
Top
 Abstract
 Introduction
PET imaging
 Perfusion imaging with tracers
 PET perfusion imaging with...
 PET tracer imaging of...
 Tracers for molecular imaging...
 Summary and conclusions
 References
 
Surrogate markers of clinical outcome are important in anticancer drug research, since clinical criteria of response develop only slowly and may be confounded by processes other than drug effect [1]. The need for surrogate outcome markers is especially great with newer agents that may act by tumour stabilization as opposed to shrinkage [2]. Neoplastic angiogenesis is associated with a number of detectable changes at molecular and microcirculatory levels. Therefore, direct study of angiogenic molecular biology and tumour circulation before during and after treatment may offer useful surrogate markers for vascular-targeted therapies. Several technologies offer image-based data on angiogenesis and vascular function. The choice of modality involves trade-offs between anatomical resolution, functional specificity and practicality. The main advantage of radiotracer imaging with positron emission tomography (PET) is its functional specificity. PET with 15O-oxygen and related tracers offers direct physiological measurement of circulatory parameters of regional blood flow and vascular volume. Labelled components of angiogenetic signalling pathways offer molecular biological imaging of new vessel formation. Recent developments with combined PET–CT camera technology are reducing some of the challenges associated with the comparatively poor anatomical resolution of PET. PET scanning protocols offer patients a level of acceptability intermediate between conventional anatomical imaging and invasive clinical pharmacology by plasma monitoring and tissue biopsy. This article will review two main areas: (a) the methodology behind PET imaging of tumour blood supply with 15O-oxygen labelled compounds; and (b) newer tracers in development as markers of angiogenetic biology.


   PET imaging
Top
 Abstract
 Introduction
 PET imaging
Perfusion imaging with tracers
 PET perfusion imaging with...
 PET tracer imaging of...
 Tracers for molecular imaging...
 Summary and conclusions
 References
 
The physical rationale and principles of human in vivo imaging with PET have been extensively reviewed elsewhere [3]. In brief, PET radiotracers are physiologically and pharmacologically relevant compounds labelled with proton-rich atomic isotopes. These are internalized by injection or inhalation, and decay by emission of a positron (positively charged electron). The positron travels a millimetre-scale distance in human tissue before combining with a normal electron, resulting in annihilation of both particles and their conversion to two 511 keV photons at almost 180° separation. The gamma ray photons arrive "coincidentally" (within a narrow window of time) at the PET camera, a ring-shaped array of photoelectric crystals. The raw PET scan data are the set of coincidental photoelectric events, logged for time and location. Using tomographic reconstruction algorithms, a computer can reconstruct the spatiotemporal distribution of the radioactive source. In contrast to the single gamma emitters of conventional nuclear medicine, the dual gamma photons of PET offer increased spatial information. This outweighs the loss of accuracy from the distance between source of positron emission and locus of annihilation. Even so, anatomical resolution (approximately 3–7 mm in current scanners) is noticeably poorer than that achieved by CT or MRI. Hence the lesions investigated by PET need to be moderately large to avoid partial volume effects (spillover of signal from adjacent tissues). Although qualitative PET findings may be apparent on the 5 mm scale, candidate lesions for quantitative PET investigation need to be at least 2 cm in diameter. This is to ensure an adequate volume dataset within the investigated "region of interest " (ROI), plus a surrounding rim of uncontaminated tissue. Newer generation cameras have combined PET and CT capability, enabling "co-registration" of the two forms of image in the same study [4]. This offers an immediate gain in data interpretation. The benefits of PET–CT for quantitative studies so far consist in improved anatomical definition of the region of interest for analysis, and more rapid calculation of the radiation-attenuating effect of tissues intervening between camera and source [5].

From the patient's perspective, PET perfusion scans are moderately demanding. The protocol currently used by our group involves almost 3 h contact on each occasion, consisting of:

During the course of the study approximately 170 ml of blood are sampled, and an estimated 9.5 mSv of radiation are absorbed. This radiation dose approaches 5 year background exposure in the UK, and is comparable with modern multislice CT protocols [6, 7].


   Perfusion imaging with tracers
Top
 Abstract
 Introduction
 PET imaging
 Perfusion imaging with tracers
PET perfusion imaging with...
 PET tracer imaging of...
 Tracers for molecular imaging...
 Summary and conclusions
 References
 
The central relationship between blood flow and tissue clearance of circulating tracers was described by Fick in 1870 [8], and can be expressed as: Go


{760S50E001}

where:

Ct=Cumulative tissue clearance, mol.mltissue–1

Ci=Influx concentration, mol.mlcarrier–1

Ce=Efflux concentration, mol.mlcarrier–1

P=Perfusion mlcarrier.min–1.mltissue–1; (perfusion is carrier flow adjusted for the volume of tissue).

In literal terms, the amount of tracer cleared by the tissue over time t is the product of perfusion P and tracer extraction . Perfusion is calculated simply by rearranging so that Go


{760S50E002}

Fick derived this model in the 19th century for use with respiratory oxygen as an indicator of cardiac output, i.e. whole body blood flow. Subsequent data have demonstrated its relevance on ever-smaller scales — now down to specific ROIs within lesions. This is not to underestimate the increasing analytical demands imposed in extracting quantitative physiological data from qualitative images (Figure 1Go). A major advantage of radiotracers is non-invasive direct measurement of tissue concentration Ct. Many experimental designs simplify the relationship such that one or all of the terms in Equation 2Go are constant (Figure 2Go). Indicator fractionation methods model Ci as arterial concentration (Ca), and Ce as the concentration in tissue fluid (Ct). 11C-microsphere fractionation studies rely on central arterial injection of radiolabelled microspheres of approximately 10 µm diameter [9]. Because effectively all tracer lodges in capillaries, Ce can be taken as zero. A number of peripherally injected PET tracers exhibit microsphere-like handling and so are suitable for work in humans. Three candidate compounds have been evaluated primarily for the myocardium and to a lesser extent brain. 62Cu-PTSM (62Cu-pyruvaldehyde bis(N4-methylthiosemicarbazonato)-copper(II)) can be generated at distance from a cyclotron using a proprietary reaction kit. Its 9.3 min half-life facilitates accurate signal counting in prolonged single-scan protocols. Unfortunately its propensity for binding to serum albumin led to underestimation of human myocardial perfusion at high rates of flow. Similarly, 13N-labelled ammonia is rapidly cleared from the vascular space by active transport and passive diffusion, and is metabolised in both normal and diseased cardiac myocytes by the glutamic acid-glutamine pathway. The half-life of 13N of 10 min supports a statistically accurate long scan, but the isotope requires synthesis in a cyclotron. The dependence of this method on specific aspects of metabolism makes it potentially less robust for non-cardiac work [10, 11]. 82Rb-Rubidium has a 76 s half-life and can be produced at distance in a column generator [12, 13]. Its limitation is emission of more energetic positrons that have a longer range in the tissues and hence yield poorer resolution images. This makes 82Rb perfusion data more vulnerable to heterogeneity within the imaged ROI, and hence less attractive for oncological work as will be seen below.



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  		Figure 1. From qualitative to quantitative in PET imaging with 15O-water.

 


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  		Figure 2. Measurement of perfusion: earlier radiotracer methods.

 
Of primarily methodological interest, indicator washout studies rely on direct administration of tracer to the tissues. In 133Xe washout dissolved radioactive 133Xe gas is injected into the tumour or a major feeder artery, e.g. the carotid artery for hemicerebral studies. Within Fick's equation, Ci is modelled as the concentration in tissue fluid (Ct) and Ce as regional venous concentration (Cv). Because effectively all tracer is exhaled at first pass through the lungs without re-circulation, Ca can be disregarded [14]. However the assumptions of this model are sensitive to assumptions including sequestration of the tracer in fat and the profile of lymphatic drainage. Other washout indicators such as heat energy although technically simple have low anatomic resolution and poor specificity for anything other than superficial lesions [15].


   PET perfusion imaging with 15O-water
Top
 Abstract
 Introduction
 PET imaging
 Perfusion imaging with tracers
 PET perfusion imaging with...
PET tracer imaging of...
 Tracers for molecular imaging...
 Summary and conclusions
 References
 
15O-oxygen
15O is the longest-lived positronic oxygen isotope, with a half-life of 123 s. It is generated via a deuteron beam in the same 10–30 MeV medical cyclotrons used for PET with 18F-fluorine [16]. 15O can be further reacted with carbon or hydrogen to produce C15O2, C15O, or H215O. In view of the rapid rate of radioactive decay, gases are piped directly to the scanner and the H215O hydrogenation reaction is set up at the bedside [17, 18]. H215O satisfies the requirements for a tracer of perfusive flow in the fullest sense of Fick's model as it is freely diffusible into and out of tissue water, biologically inert (no net effect on structure or function), and metabolically inert (not itself modified by or retained in the tissues). Based on these characteristics "tissue water" can be modelled as a single compartment comprising both tissue and its draining fluids the veins and lymphatics.

15O-steady-state method
The steady-state method of Frackowiak and colleagues, though now superseded as a result of improved PET scanner technology, illustrates the basic model for perfusion imaging with 15O-water [19]. Subjects inhale radioactive 15O-carbon dioxide, and this is converted in the lungs by carbonic anhydrase to 15O-water. After 5 min equilibrium is reached, when 15O-water arterial influx is balanced by efflux and isotope radiodecay. After this point increasing accuracy of measurement is simply a matter of prolonging data acquisition, typically for a further 5 min at each of four bed positions in an early generation limited field-of-view scanner. The concentration of tissue radioactivity in the ROI can then be described as: Go


{760S50E003}

where:

Ct=Tissue radiotracer concentration, Bq.mltissue–1 (SI unit of radioactivity is the Becquerel (Bq); counts.s–1).

Ca=Arterial radiotracer concentration, Bq.mlblood–1

P=Perfusion, mlblood.min–1.mltissue–1

{rho}=Partition coefficient for water: the proportionality constant for concentration when tracer equilibrates between tissue fluid and a unit volume of blood, mltissue.mlblood–1.

{lambda}=Radioactive decay constant for 15O, 0.338 Bq.min–1.Bq–1. This is defined as "the fractional reduction in radioactivity over a given time interval"; i.e. for every Bq of 15O2 activity at t=0 min, 1–{lambda} Bq remain at t=1 min.

The basic logic of the model is to propose three terms accounting for tissue radiation flux in Bq.mltissue–1.min–1. In other words Go


{760S50E004}

This concept is illustrated in Figure 3Go.



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  		Figure 3. Tracer measurement of perfusion: steady-state H215O method.

 
In most accounts however Equation 3Go is rearranged so that Go


{760S50E005}

which is usually given as Go


{760S50E006}

since {rho} is assumed to equal 1.

Ct can be measured from the image, as can Ca if a large arterial pool such as the left atrium is in view; otherwise Ca can be measured by radial arterial sampling. Significant levels of arterial blood activity within the imaged ROI can be corrected by adding a term for arterial volume Va, such that Go


{760S50E007}

where CROI is concentration in the imaged ROI.

The steady-state model's key limitation is the assumption about {rho}, the proportionality constant for tissue-blood concentration. This leads to underestimation of flow especially in tumours, many areas of which are likely to exhibit low values of {rho} [20, 21]. Additionally, achieving and maintaining equilibrium requires prolonged administration of radiation resulting in approximately twice the systemic dose than is received with bolus administration [19]. Intrathoracic tissues may also be difficult to image on account of spillover of radioactivity from inhaled C15O2 gas in the lungs. By contrast, local signal contamination with intravenously injected radiotracers is mainly confined to the site of cannulation in peripheral veins [22].

15O-dynamic water method
Use of changing blood tracer data to support calculations of cerebral blood flow had been pioneered by Kety and Schmidt in the 1940s [23]. Improvements in scanner technology in the 1980s enabled Lammertsma and colleagues to extend these methods to PET [24]. Their 15O-dynamic water method replaces population assumptions about {rho} with direct measurement and so can be regarded as the current benchmark approach for imaging perfusion with 15O-water. The tracer is administered by inhalation or more commonly now by bolus peripheral venous injection. The PET scanner follows the curve of changing tissue radioactivity over the next 10 min. Continuous arterial data are obtained either by imaging a great vessel or by peripheral sampling to a well counter device [25]. In the case of peripheral sampling a correction needs to be made for "delay and dispersion" of the recorded arterial curve, consequent on the transit of blood through approximately 1.2 m of connecting tubing. This imposes not only a delay but also dispersion or widening of the curve on account of slower rate of laminar flow at the margin of a tubular vessel [26].

The change in tissue concentration over time is modelled as: Go


{760S50E008}

where:

VD="Volume of distribution", the "proportion of the region of interest in which the radioactive water is distributed", mlblood.mltissue–1 — effectively {rho} as its reciprocal.

Ct(t)=Instantaneous tissue concentration of H215O at time t, Bq.mltissue–1

Ca(t)=Corrected instantaneous arterial concentration of H215O at time t, Bq.mltissue–1.

The mathematics for solving P and VD from the dynamic curves are inexact as they depend on convolution of the arterial and tissue datasets. The expression for tissue concentration at each time t is given by the convolution integral: Go


{760S50E009}

more commonly written as Go


{760S50E010}

where{otimes}is the operation of convolution. The general form of a convolution integral is as follows: Go


{760S50E011}

Ct(t) describes a biphasic curve with an initial peak followed by a longer tail of decay. P and VD can be determined from the curve using non-linear least-squares fitting. A rationale for the model is illustrated in Figure 4Go.



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  		Figure 4. Tracer measurement of perfusion: dynamic H215O method.

 
The dynamic method has been shown to be less sensitive to tissue heterogeneity than its steady-state predecessor [21]. Because equilibrium is not reached it is more sensitive to assumptions about constancy of P and VD, and free and instantaneous diffusion of 15O-water out of arterial blood and through the tissues, i.e. that the arterial extraction fraction is unity, and that tissues exhibit neither tracer binding nor concentration gradients.

The concept of VD (likewise {rho}) has yet to be validated against other physiological parameters. From first principles VD is expected to reflect tissue water composition and handling. Thus in fatty tissues VD should be low, whereas in water-secreting tissues such as the renal cortex it should be high. VD that is disproportionately low for a given tissue type should suggest the presence of ischaemic or necrotic areas. There is currently no method that will quantitatively predict the contributions of such factors to VD. There is however considerable experimental justification for the use of these factors as explanations. For example, dynamic 15O-water PET studies found markedly lower VD in breast, a fatty tissue, than in spleen or kidney [27]. Furthermore the ratio P/VD, which could be regarded as an index of "physiologically relevant perfusion", insofar as fatty tissues have a lower respiratory rate, was similar between breast tumour and normal breast tissue.

Comparability and validity of 15O-water methods
In the 1980s the 15O-water steady-state water method was compared with conventional measures of human regional cerebral blood flow in a series of studies evaluating published literature data, canine 11C-microspheres, primate intracarotid 15O-water injection, and human 11C-microspheres [9, 19, 28, 29]. Similar comparisons were made for myocardial blood flow with 11C-microspheres in dogs and humans [30–34]. A smaller number of results have also been published for skeletal muscle, kidneys, and spleen [35, 36]. The dynamic method was assessed initially for the brain and myocardium and then for breast tumours [26, 27, 33, 37, 38].

The 15O-water data on perfusion of tumours of brain pancreas and liver are compatible with data from those diseases investigated using other means, and the range of values reported by PET for tumours is likewise within the reported range for PET in other tissues. The immediate challenge for improved validity of the technique lies in the handling of heterogeneity of tumour blood flow. In this respect the assumption of a single arterial input and equilibration of arterial and tissue water is not fully in step with histological evidence about the tumour microcirculation. Data such as the long tail of values for oxygen content in venous erythrocytes attest to heterogeneity of tumour blood supply on microscopic scales, with such phenomena as shunts, ischaemia, and necrosis [39]. For this and other reasons a major goal of current research is to develop a reliable PET tracer of tissue hypoxia (q.v.).

Reproducibility of the dynamic 15O-water method and published experience
Table 1Go summarizes the reproducibility data that have to date been published on the dynamic 15O-water method [40]. These can be used to support sample size calculations for design of "before and after" studies assessing the impact of antivascular interventions on perfusion. Table 2Go summarizes the small number of such interventional studies that have to date been reported. At this time it is not absolutely clear how we should expect PET measurements of tumour perfusion to change in response to therapy or even the natural history of the disease. Some baseline data on the effects of standard cytotoxic therapy on tumour perfusion are starting to appear. Miller and colleagues studied 70 breast cancer patients who had cytotoxic chemotherapy with a sequential regimen of bolus Docetaxel either before or after Doxorubicin. 19 of these patients underwent PET with 15O-water before, during and after chemotherapy. A preliminary report has found no association between pattern of response to therapy and the semiquantitative ratio of perfusion between tumour and contralateral normal breast. Tumour blood volume measured with 11C-carbon monoxide increased in responding patients but decreased in non-responders. Results of dynamically modelled data are awaited [41]. The ultimate utility of PET methods as a measure of tumour perfusion will depend on their ability to demonstrate changes that predict for clinical outcome with targeted antivascular treatment. We expect these data to emerge over the next 5 years.


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  		Table 1. Between study comparison of H215O PET tumour perfusion and VDc

 

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  		Table 2. PET perfusion before and after therapy

 

   PET tracer imaging of tissue hypoxia and vascular volume
Top
 Abstract
 Introduction
 PET imaging
 Perfusion imaging with tracers
 PET perfusion imaging with...
 PET tracer imaging of...
Tracers for molecular imaging...
 Summary and conclusions
 References
 
PET imaging of hypoxia
The principal strategy for tracer imaging of tissue hypoxia to date has involved use of compounds that are preferentially absorbed and trapped within cells in the reduced state. Within this group there has been the widest experience with nitroimidazoles, and amongst candidate PET tracers with 18F-fluoromisonidazole (18F-MISO). This tracer has been used to image hypoxia in human tumours in vivo and to monitor the effects of conventional therapy [42–44]. Unfortunately 18F-MISO has less than ideal tracer characteristics, with a limited rate and extent of uptake into hypoxic tissue meaning that it takes between 2 h and 4 h to achieve an adequate target/background ratio for imaging. Accordingly a number of alternative tracers are in development, including non-nitroimidazole possibilities [45–47].

Vascular volume imaging with C15O
C15O-carbon monoxide binds irreversibly with haemoglobin to form C15O-Hb carboxyhaemoglobin. This remains exclusively within the vasculature and therefore can be used as a tracer of vascular volume. The subject inhales a fixed dose of C15O through a loose-fitting mask, then breathes room air for approximately 90 s while arteriovenous carboxyhaemoglobin levels equilibrate. A tissue concentration dataset is then obtained over a further 5–6 min with the PET scanner. An arterial C15O-Hb concentration curve is constructed from a series of discrete blood samples over the same interval. Tissue vascular volume can be defined as Go


{760S50E012}

where

Vv=volume of vessels, mlvessels

Vt=volume of tissue within ROI on scan, mltissue

R=ratio of small vessel to large vessel haematocrit (assumed to be 1 in tumours [48])

{int}Ct(t)=integrated tissue activity during period of scan, Bq.ml–1.min

{int}Ca(t)=integrated arterial activity during period of scan, Bq.ml–1.min

Vascular volume data are of obvious interest in relation to therapies such as Combretastatin that may exert their effect via frank collapse of blood vessels, as opposed to reduced flow through isovolumetric vessels [49]. Their value in the case of capillary-directed antiangiogenetic therapies is less certain, given histological evidence that capillaries account for only a minor part of total tumour blood volume.


   Tracers for molecular imaging of tumour angiogenesis with PET
Top
 Abstract
 Introduction
 PET imaging
 Perfusion imaging with tracers
 PET perfusion imaging with...
 PET tracer imaging of...
 Tracers for molecular imaging...
Summary and conclusions
 References
 
Molecular imaging offers serial non-invasive lesion-based evaluation of tumour parameters. In the case of the "physiological" tracers discussed in previous paragraphs, these parameters reflect proximate outcomes of anti-angiogenetic treatment. Molecular imaging of angiogenetic signalling pathways promises to go one step further by evaluating specific aspects of tumour vascular biology. In theory it might be possible to label and image any part of the intercellular signalling axes and local genetic processes underlying neoplastic angiogenesis. Paradoxically, high specificity in itself poses a significant challenge to this field. Although it may be feasible to set up chemical syntheses in which radioisotopes are bonded to candidate organic compounds, at the present time PET tracer discovery parallels that of any other pharmaceutical in terms of its risk, cost, time, and labour-intensity. Various pharmacokinetic considerations affect the choice of basic tracer molecule. In the case of endothelial biology there may be an intrinsic advantage to large (molecular weight>120 kDa) molecules such as monoclonal antibodies (MAbs) since many relevant tracer targets are "visible" from the vascular space. This makes non-specific tracer diffusibility disadvantageous, insofar as leakage across vessels can lead to non-specific tissue accumulation [50, 51]. In the pharmacodynamics domain each new tracer must be validated for its correlation to a clinically relevant event in tumour angiogenesis. Finally, the decision to proceed with development of a new tracer depends strongly on an expectation that the specific target it images will still be generically relevant in 10 years' time.

Despite these caveats, the main directions of future anti-angiogenetic treatment are taking shape and suggest promising areas for biological PET tracers. These can at present by classified under the headings of thymidine kinase pathways, matrix metalloproteases (MMPs) and cellular integrins.

Thymidine kinase pathways
Upregulation of the vascular endothelial growth factor (VEGF) and or fibroblast growth factor (FGF) systems has been reported in virtually all human tumours examined, and correlates with standard histological indices of vascularity [52]. VEGF is a highly specific mitogen for vascular endothelial cells, its activity being mediated by a family of transmembrane receptor tyrosine kinases (VEGF-R) [53, 54]. It is apparent that there are "tumour-specific profiles" for the specific subclasses of these systems that are activated [55, 56]. This finding may influence the choice of specific VEGF or FGF-related tracer for imaging applications. In theory such profiles should be less subject to clonal selection by treatment as they are a function of the stroma and not the tumour itself. VEGF subtypes 165 and 121 have been labelled with the gamma emitter 123I. VEGF165 capacity was prominent in a greater range of tumours making this the more promising tracer for future therapy monitoring [57]. The anti-VEGF monoclonal antibody VG76e has been labelled with the PET tracer 124I, and following successful validation in a mouse model is now ready to proceed with studies in humans [58]. FGF-1 labelled with gamma emitting 99Tcm in rats showed high liver uptake reduced by heparin and is therefore also plausible as a tracer [59]. It could potentially be labelled with a positron emitting metal such as copper. Likewise, gamma-emitting 111In-3H3 FGF-2 mouse MAb was specifically retained in tumours with an FGF-2-positive profile [60].

Tissue inhibitors of metalloproteases (TIMPs)
The agent TIMP-2 has been labelled with 111In-DTPA and safety, biodistribution and dosimetry profiles supported its clinical diagnostic use. The results are awaited of imaging studies conducted in MMP expressing tumours [61].

Integrin receptor pathways
Endothelial cell integrins often recognise the peptide sequence Arg-Gly-Asp (RGD). This forms the basis of a number of strategies using synthetic RGD peptides to visualize the v3 receptor. The body of experience to date has been with gamma-labelled peptides P2, RP593 and DTPA-c(Arg-Gly-Asp-D-Tyr-Lys) [62]. So-called second-generation peptide tracers have been pharmacokinetically improved by glycosylation. These include the agents GP2 and RGD glycopeptide cyclo[-Arg-Gly-Asp-D-Phe-Lys(sugar amino acids)-] [63]. Although negative results were reported with the tracer 99Tcm-vitaxin (a humanized anti-{alpha}v{beta}3 antibody), this was in a study in which no patient responded to therapeutic doses of the agent [64].


   Summary and conclusions
Top
 Abstract
 Introduction
 PET imaging
 Perfusion imaging with tracers
 PET perfusion imaging with...
 PET tracer imaging of...
 Tracers for molecular imaging...
 Summary and conclusions
References
 
This article has aimed to illustrate how PET can provide direct measurement of physiological parameters relevant to malignant angiogenesis and its therapy. 15O-water is currently the most validated tracer system for this application, is reasonably convenient to use in the research setting, and is supported by a number of theoretical considerations. This is therefore a tool that is ready for final evaluation as a surrogate marker of vascular tumour response in support of new cancer drug development. 15O-water studies may soon also be usefully combined with newer tracers reporting other aspects of vascular tumour response. The place of PET as a research tool will depend on evidence of its efficiency and effectiveness in supporting the timely development of new therapies by industry. Changing regulatory requirements for drugs may also have a part to play, insofar as data are required that agents conform to their stated mode of action. It seems less likely that current PET protocols, at least those with short-lived 15O tracers, will have a role in routine patient care. However it may well be that decisions on specific vascular-targeted anticancer therapies will one day be demonstrably supported by one of the newer or alternative PET vascular tracers.


   Acknowledgments
 
Many thanks to Professors Terry Jones and Vin Cunningham and Dr Chris Rhodes for helpful comments during drafting of this work.


   References
Top
 Abstract
 Introduction
 PET imaging
 Perfusion imaging with tracers
 PET perfusion imaging with...
 PET tracer imaging of...
 Tracers for molecular imaging...
 Summary and conclusions
 References
 

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