Recent advances and future projections in clinical radionuclide imaging.

1990, The British Journal of Radiology, 63, 411-429

VOLUME 63 NUMBER 750

JUNE 1990

The British Journal of Radiology Review article Recent advances and future projections in clinical radionuclide imaging By A. M. Peters Department of Diagnostic Radiology, Royal Postgraduate Medical School, Hammersmith Hospital, Du Cane Road, London W12

(Received August 1989 and in revised form January 1990)

Since the almost simultaneous development of technetium-99m and invention of the gamma camera in the 1960s, nuclear medicine has made great strides. It is largely a physiological imaging modality, so a thorough grounding in physiology is essential for aspiring nuclear physicians. In contrast, computed tomography (CT), ultrasound, magnetic resonance imaging (MRI) and special radiographic techniques, like angiography, currently provide largely anatomical information. Advances in nuclear medicine can be subdivided into seven areas: new synthetic radiopharmaceuticals, new radiolabelled biological agents, cell labelling, new singlephoton-emitting radionuclides, new approaches using radiopharmaceuticals that are already well established, positron emission tomography (PET), and physics and instrumentation. The important developments in radiopharmaceuticals have had the common aim of replacing well-established agents labelled with radionuclides other than technetium-99m with agents that can be labelled with technetium-99m and which have similar pharmacokinetics. They include technetium-99m hexamethylpropyleneamine oxime (HMPAO), which will replace iodine-123 labelled amphetamines (themselves relatively new) for imaging brain perfusion, and also partly replace the indium-Ill complexes for imaging inflammation. Others are mercaptoacetyltriglycine (MAG-3) which should replace radioiodinated hippuran for renography, the isonitriles which may replace thallium-201 for myocardial perfusion imaging, and the "pseudo-gases", such as technegas, which may replace krypton-81m for routine ventilation imaging. The need for these technetium-99m radiopharmaceuticals is due not so much to their superior pharmacokinetics (where, in fact, they are generally somewhat inferior to their non-technetium counterparts) but to considerations of convenience, camera design and image resolution, dosimetry, and ultimately cost; although, at present, they are expensive. The recent dependence of nuclear medicine advances on cell biology and immunology contrasts with their Vol. 63, No. 750

earlier (and continuing) dependence on radiochemistry and physics. Radiolabelled monoclonal antibodies and autologous blood cell labelling are the best examples of the former. The British Nuclear Medicine Society Meeting in 1980 included three papers on cell labelling and none on monoclonal antibodies, whereas in 1988 they were both as well covered as any other speciality. Other exciting developments based on complex biological materials are on the way, for example, labelled serum amyloid protein for imaging amyloid deposits. There has been relatively little activity in the development of new single-photon-emitting radionuclides. Technetium-99m is so well established that new radionuclides are likely to be in the ultra-short-lived category and therefore generator produced, such as gold-195m (half-life 30 s), recently introduced for rapid sequential first pass cardiac studies. The cost of purchasing and running the PET scanner still limits the more widespread use of positron imaging in spite of its potential for metabolic tracer imaging and physiological studies. Advances in technology should reduce its cost and increase its availability. We are still seeing novel applications of established radiopharmaceuticals. Captopril renography is an example. These approaches emphasize the physiological nature of isotope studies and there are likely to be further developments of functional imaging in association with pharmacological stimulation and suppression. The urinary system

The most important recent development in nuclear medicine of the urinary tract is the introduction of MAG-3 (Jafri et al, 1988; Taylor et al, 1988). This is a technetium-99m labelled mimic of hippuran, one of the oldest and most widely used radiopharmaceuticals. However, the difficulty with hippuran is that it can only be labelled with radioiodine: iodine-123 still has limited availability while iodine-131 is radiotoxic and has an energy too high for modern gamma cameras, resulting 411

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in poor image resolution. The main advantage of hippuran is its optimal pharmacokinetics for renal imaging. Thus its renal extraction fraction exceeds 80%, which, with its partial protein binding in plasma, combine to give excellent target-to-background activity ratios. It is excreted in urine as a result of glomerular filtration and tubular secretion and is therefore useful for studies of renal drainage. MAG-3 has pharmacokinetic properties similar to those of hippuran. Although its renal extraction fraction, at 60%, is less than hippuran's, this is compensated by a greater degree of protein binding in plasma, resulting in a smaller volume of distribution and consequently a half-time of whole body clearance similar to that of hippuran (Jafri et al, 1988; Taylor et al, 1988). The renogram can conveniently be divided into three phases: flow, filtration and drainage, rather misleading terms which are better termed 1, 2 and 3. Phases 1 and 2, since they give information on renal blood flow (RBF) and glomerular filtration rate (GFR) respectively, can be thought of as the medical phase, and 3, which gives information on drainage, as the surgical phase. Technetium-99m diethylenetriaminepentacetic acid (DTPA) remains an important radiopharmaceutical for the medical phase because, since it is handled like inulin, it is still the only renal imaging radiopharmaceutical which gives specific quantitative data on GFR. MAG-3, however, although it reflects a variety of functional parameters, gives better images than DTPA and it is to be preferred for urological indications, especially when function is impaired. The quality of MAG-3 images during the parenchymal phase (i.e. that part of the renogram up to about 3min when activity first appears in the collecting system), although better than DTPA, is still inferior to that of technetium-99m dimercaptosuccinic acid (DMSA), which remains an important radiopharmaceutical for nephro-urological use. The principal clinical problem in renal allograft imaging is the identification of rejection, and in particular distinguishing it from cyclosporin nephrotoxicity. High hopes were pinned on platelet scintigraphy, but, although in early studies marked platelet uptake was demonstrated in rejection, some groups later reported that such uptake could also be seen in cyclosporin nephrotoxicity (Leithner et al, 1986). This is a controversy that remains unresolved (Collier et al, 1988), partly because of the high degree of motivation required to perform the relatively large numbers of platelet studies required in this setting. The development of radiolabelled antiplatelet and antifibrin monoclonal antibodies, which can be given intravenously, may resolve this problem. There is no doubt that a simple approach which would rapidly diagnose acute rejection would be of great clinical value. A new application in nuclear nephrology is the Captopril stimulation test for the diagnosis of renovascular hypertension (RVH) (Geyskes et al, 1987; Wenting et al, 1987). The impetus for this test came from interventional radiology and the readiness to attempt revas412

cularization of the kidney by percutaneous transluminal renal angioplasty (PTRA) (Klinge et al, 1989). The almost simultaneous development of digital vascular imaging, which enables screening for renal artery stenosis (RAS) with intravenous contrast on an out-patient basis, has also contributed to increased awareness of renovascular disease as a cause of hypertension. The main problem facing the interventional radiologist is the prediction of the response to PTRA in terms of blood pressure control. In a recent review, Sherwood (1988) highlighted this problem by estimating that only about 8% of patients with angiographic evidence of atherosclerotic RAS ultimately benefitted from PTRA, although thisfigureis higher in younger hypertensives in whom fibromuscular hyperplasia is more common. The current interest in Captopril arises from the realization that no tests, invasive or otherwise, not even renal vein renin levels (Carmichael et al, 1986), are able to predict the response to PTRA accurately. Conventional radionuclide investigations are of limited value. It has been shown that there is no correlation between RBF or individual kidney GFR and renal angiography within a hypertensive population (Peters et al, 1988). Parenchymal transit time is elevated in functionally significant renovascular disease (Al-Nahhas et al, 1989), but this is difficult to measure and of uncertain specificity. The principle underlying the Captopril test is as follows (Levenson & Dzau, 1987). As a result of obstruction in the renal artery, the intravascular pressure is reduced distal to the stenosis. This results in an increased production of renin which, through angiotensin, mediates post-glomerular (efferent) arteriolar vasoconstriction. This minimizes the pressure gradient across the arterial stenosis and raises the filtration pressure, maintaining GFR at the expense of a further reduction in RBF. Captopril is an angiotensinconverting enzyme (ACE) inhibitor and so blocks renin. A single oral dose of Captopril is capable of almost abolishing GFR in an ischaemic kidney responsible for systemic hypertension. A baseline renogram is performed to establish the functional status of the two kidneys. The following day, renography is repeated 1 h after an oral dose of Captopril. A positive response is one in which there is evidence of a substantial fall in GFR in the abnormal kidney (Fig. 1). RBF usually increases, even in normal kidneys, and is not a useful discriminator between essential hypertension and renovascular hypertension, although more work on this is needed. A major difficulty in understanding the literature on Captopril renography arises from the failure of authors to distinguish RVH clearly from RAS. Many normotensive patients have RAS (Eyler et al, 1962; Holley et al, 1964), and probably less than 40% of hypertensive patients with RAS have RVH, defined as an improvement in blood pressure following revascularization (Brawn & Ramsay, 1987). In RVH of long-standing, further damage to the kidneys as a result of hypertension is likely to blur the The British Journal of Radiology, June 1990

Recent advances and future projections in clinical radionuclide imaging

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distinction between essential hypertension and RVH and ultimately blunt any benefit that may be gained from revascularization. It is for this reason that making a diagnosis of RVH is of less importance than predicting the response to PTRA, and this reinforces the need to find a predictive test. It remains to be seen whether Captopril renography will fulfil this need. Vol. 63, No. 750

Figure 1. Positive Captopril technetium-99m DTPA renography in a patient with suspected renovascular hypertension, (a) Baseline study. Image acquired about 3 min after injection of technetium-99m DTPA shows an essentially normal right kidney and small, poorly functioning left kidney. Differential glomerular filtration was left = 22%, right = 78%. (b) Repeat study, following day, 1 h after 25 mg Captopril by mouth. The right kidney remains essentially normal. The left kidney, although maintaining a normal blood flow (not shown), almost completely stopped filtering, (c) Three weeks later, following revascularization, differential function was almost equalized. The patient's hypertension improved.

Infection

Radionuclides are used in a largely non-specific way for the diagnosis of infection, such as technetium-99m DMSA in urinary tract infection, technetium-99m methylene diphosphonate (MDP) for osteomyelitis and, earlier, liver/lung scanning for subphrenic abscess. Gallium-67 was the first radionuclide to be used more 413

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specifically. This, however, also localizes in neoplastic tissue, especially lymphoma, gives images of poor resolution, and cannot provide a diagnosis of infection much earlier than 48 h after the clinical request. Against this background, indium-Ill labelled leucocytes made quite a spectacular entrance into nuclear medicine in the late 1970s (Thakur et al, 1977). The principle of leucocyte scanning is that, following their injection, autologous white cells, previously isolated from peripheral blood and radiolabelled in vitro, target sites of inflammation and migrate into them. The technique has been refined since its introduction so that an accurate diagnosis of sepsis is now available from a white cell scan within a few hours of the request. We also have a better understanding of its limitations, such as in chronic inflammation, in which the neutrophil turnover may be too slow for enough label to be accumulated within the intravascular life span of the labelled cell. The clinical areas where indium-Ill leucocyte scans have made the greatest impact are inflammatory bowel disease (IBD), intra-abdominal sepsis, osteomyelitis (in particular the infected prosthetic hip) and, to a lesser extent, pyrexia of unknown origin (PUO) (Peters & Saverymuttu, 1987). White cell scanning is very useful for screening patients for IBD and should be used early in their evaluation with the aims of diagnosis, definition of extent and quantification of disease activity. They are particularly useful for distinguishing relapse from other, unrelated, causes of acute illness and from mechanical strictures. Labelled leucocytes are less useful in PUO than one might imagine because only a minority of PUOs have an infective cause, most of which are not pyogenic anyway. Gallium-67 may be at least as useful since it has the potential for detecting most infective causes in addition to other pathologies, such as lymphoma, which may cause PUO. A recent development in white cell scanning has been the introduction of technetium-99m HMPAO (Costa et al, 1988; Roddie et al, 1988). This agent was initially developed for imaging cerebral perfusion but, by virtue of its lipophilicity, readily penetrates blood cells. Following cell penetration, the complex becomes trapped as a result of a decrease in lipophilicity. Apart from the advantages of technetium-99m over indium111, which include lower radiation dose, better image resolution (Fig. 2), greater convenience and potentially lower cost, technetium-99m HMPAO labels cells with a reasonable efficiency in plasma enriched media and, furthermore, labels granulocytes with some degree of selectively and greater stability than other blood cells. This agent is replacing indium-Ill for white cell scanning in a number of centres. It will not replace it entirely, however, for two reasons. Firstly the short halflife of technetium-99m precludes quantitative studies, such as faecal granulocyte excretion in IBD, and secondly because it has difficulty in identifying septic foci which are draining spontaneously via an enteric communication (Saverymuttu et al, 1985a). This difficulty arises partly from the short half-life and partly

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from the excretion of secondary HMPAO complexes into the gut from about 4 h onwards. Advances in the imaging of inflammation will probably follow two pathways. The first is the widening applications of labelled neutrophils both in a routine clinical setting and in clinical research. Many of these applications are in chest medicine such as adult respiratory distress syndrome (Becker et al, 1989a), bronchial asthma and lobar pneumonia (Saverymuttu et al, 1985b). Others include neutrophil migration into rheumatoid joints (Uno et al, 1986) and localization in recent myocardial infarction (Bell et al, 1987). The importance of these applications lies in the potential for tissue damage as a result of migrating neutrophils. The possibility of selective labelling of subsets of leucocytes such as eosinophils, lymphocytes and monocytes, without damaging them, also merits further investigation. The other pathway, which should be explored with some urgency, is the development of agents capable of specifically labelling neutrophils in vivo, thereby avoiding the need for in vitro manipulation of autologous blood. One such approach, which has been shown to be feasible for platelet labelling (see below), is the use of radiolabelled monoclonal antibodies recognizing surface antigens (Locher et al, 1986; Hasler et al, 1988; Joseph et al, 1988a,b). Two such monoclonal antibodies to granulocytes are currently in clinical trial, both capable of being labelled with short-lived tracers. These antibodies, although exciting prototypes, will need to be improved before this approach is in widespread use (Vorne et al, 1988). Thus their in vivo labelling efficiency seems very low, and their biokinetics are unclear (Becker et al, 1989b). It may well be that the monoclonal antibody targets the inflammatory focus directly rather than via the circulating neutrophil. In contrast to monoclonal antibodies, labelled polyclonal human immunoglobulin (IgG) has recently been shown to localize in inflammatory foci (Rubin et al, 1989). Like gallium-67, labelled IgG is not specific for inflammation, being also taken up by a variety of neoplasms. In addition, the target-to-background ratio in inflammatory lesions appears to be less than with labelled white cells. Nonetheless, since it is an "off" the shelf agent not requiring in vitro blood labelling, it represents a significant advance. Another technique of specifically labelling leucocytes in whole blood is by phagocytosis of technetium-99m colloid (Hanna & Lomas, 1986). Again the results are very variable, which is not surprising as phagocytosis would be expected to activate the cell prior to injection. Nonetheless, the technique should be investigated further according to the guidelines enunciated by the Australian group which has published extensively on it and claimed success with it (Pullman et al, 1986). An exciting novel approach to imaging inflammation would be to target the endothelium within inflammatory foci. The endothelium is not a passive barrier to migrating neutrophils at sites of infection but plays an

The British Journal of Radiology, June 1990

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Figure 2 Technetium-99m HMPAO white cell scanning, (a) Multiple intra-abdominal abscesses, (b) Crohn's Disease of the small bowel, (c) Pre-sacral abscess in a patient with an ileostomy. Note high resolution of the images and also the relatively high attenuation of the technetium-99m photons (pre-sacral abcess not visible on anterior view in patient) (c). Note also urinary activity

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active role, expressing cell-specific receptors in response to mediators (known as cytokines) generated in the tissues. Monoclonal antibodies are now available which recognize such receptors and which could be labelled for the purpose of imaging inflammation, representing another angle to the field of immunoscintigraphy. The lung

Lung perfusion scanning with technetium-99m macro-aggregates for the diagnosis of pulmonary embolism has, for a long time, been one of the most useful and specific applications of nuclear medicine. Progress in lung scintigraphy is moving along a number of avenues: first, the search for a ventilation agent which will give images, in multiple projections, as good as those given by krypton-81m, yet be available "round the clock"; secondly, the widening of the clinical applications of ventilation perfusion (V/Q) lung scanning with a recognition of its value in conditions other than pulmonary embolic disease; thirdly, new methods of diagnosing pulmonary embolism; fourthly, imaging of the bronchial tree; and finally, imaging the metabolic functions of the lung. Xenon-133 by inhalation is a rather poor ventilation agent for the exclusion of pulmonary vascular disease. This is to some extent the result of its low energy. Also the number of projections available is limited, unless it is inspired for short periods ("wash-in" phase only) (Diffey et al, 1986). These drawbacks led to the development of technetium-99m labelled aerosols, all of which give good images of ventilation in patients with otherwise normal lungs, but poor images, resulting from airways deposition, in patients with chronic lung disease. The newest ventilation agents are so called "pseudogases", of which Technegas is the most promising. This is, effectively, technetium-99m labelled smoke, produced by heating pertechnetate in a carbon crucible to a temperature of 2500°C (Burch et al, 1986). Following rapid cooling, the labelled carbon particles are inspired and deposited in the airways. Their relatively long biological clearance half-time, however, necessitates computer subtraction of the ventilation images from the subsequent perfusion images. Technegas should have a useful role in paediatric ventilation imaging because of the difficulty of acquiring high quality krypton-81m ventilation images in small children, most of whom have an aversion to a mask placed over the face. V/Q lung scanning in most nuclear medicine departments is performed exclusively for the diagnosis of pulmonary embolism. There are, however, a number of other useful applications. In common with nuclear medicine tests in general, V/Q scanning provides functional data which complement the structural information given by conventional radiography and CT. In paediatrics, for instance, although pulmonary embolism is uncommon, V/Q scanning plays an important role in the management of patients with asthma, sequestrated segments, inhaled foreign bodies and congenital lobar emphysema (Peters et al, 1989). 416

As mobile gamma cameras become more compact and more mobile, V/Q lung scanning in the intensive care unit could become of value, since most intensive care patients have respiratory problems which may be regional, transient and difficult to monitor by portable chest radiography. Another area where V/Q lung scanning may, in future, have an important role is in the detection of rejection following lung transplantation, a manifestation of which is bronchiolitis. Ventilation scanning alone could also play an important role in assessing the response to physiotherapy in a very large population of respiratory and post-surgical patients. Perfusion scanning for the diagnosis of pulmonary embolism is an example of negative scanning, i.e. looking for a cold area against a background of normal high activity. This places limitations of image resolution on the detectability of an abormality in contrast to positive scanning, i.e. looking for hot spots against a low background, in which the detectability depends more on the target-to-background ratio. A new approach to detecting pulmonary embolism, based on the latter principle, is the use of monoclonal antiboides which recognize platelets or fibrin. This will go hand-inhand with the development of these agents for the diagnosis of deep vein thrombosis (see below). By labelling these monoclonal antibodies with short-lived tracers, such as technetium-99m and iodine-123, it would be possible to perform single-photon emission computerized tomography (SPECT) and increase the detectability of small emboli. Alternatively, the protein could be labelled with positron-emitting metal cations for positron emission tomography (PET). Another possibility for "hot-spot" imaging of pulmonary embolism is by inhalation of aerosols of highly lipophilic tracers, the transfer into the pulmonary vasculature of which is blood flow limited rather than diffusion limited. The tracer is therefore rapidly washed out of ventilated and perfused lung, never reaches nonventilated lung, but is trapped in ventilated nonperfused lung, as in pulmonary embolism. Initial efforts with technetium-99m HMPAO have demonstrated the feasibility of this approach (Arnot et al, 1988). Inhaled aerosols whose clearance is diffusion limited have a quite different application, namely the detection of abnormal alveolar epithelial permeability (Jones et al, 1983). Unfortunately, the exquisitely high sensitivity of this latter technique detracts from its value in that, for example, smokers show a very rapid clearance. One of the growing points in nuclear medicine, in future, will be the labelling of receptors and enzymes by specific ligands that bind them (Fig. 3). This concept has been pursued with the labelling of neurotransmitter receptors in the brain with carbon-11 (positron-emitting) labelled ligands, but is now also being applied, for example, to beta adrenoreceptors in the lung. A wide variety of ligands may occupy such receptors, with agonistic or antagonistic activity or neither. The requirements of an ideal beta receptor ligand would be hydrophilicity (to maintain an extracellular location), high specifity, high affinity, the availability of a stereoiThe British Journal of Radiology, June 1990


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Figure 3. Thoracic tissue distribution of C-11 labelled acetazolamide in a dog lying on its left side. The PET images shown here were acquired sequentially at 2min intervals from a single transaxial plane. Note that the activity is initially high in the lung regions and then builds up in the myocardium. Displacement with unlabelled acetazolamide results in loss of all localization. Courtesy of Dr J. M. B. Hughes.

somer (to show stereospecific uptake), a physiological effect, and affinity for receptor subclasses which could then be separately studied by selective ligand displacement. Although the imaging of the distribution of beta receptors at present requires PET technology, the information generated is of great potential value, with respect both to diagnosis and to the study of the physiology of receptor expression and drug pharmacokinetics. It is also possible tp envisage more co-operation with the pharmaceutical industry in the pursuit of ligands which could be labelled with single-photon-emitting radionuclides. Finally, there may be diagnostic value in imaging the metabolic functions of the lung, which detoxifies a variety of mediators, such as serotonin and other amines arriving in central venous blood. Extraction efficiencies of intravenously injected radioactive labelled amines and their subsequent clearances from the lung have been quantified as indices of the metabolic function of the lung (Pistolesi et al, 1988). The potential of this approach has yet to be exploited. The cardiovascular system

An important new radiopharmaceutical for cardiac imaging is technetium-99m labelled methoxyisobutylisonitrile (MIBI) (Najm et al, 1989; Taillefer et al, 1989). Vol. 63, No. 750

Because of the high photon flux of technetium-99m compared with thallium-201, MIBI gives images of myocardial perfusion with a higher target-to-background ratio than thallium-201 and is ideal for SPECT. Unlike thallium-201, redistribution studies are not possible since the compound is more or less fixed inside the myocardial cell for a number of hours. Separate injections at rest and during exercise are therefore needed to distinguish between viable and non-viable myocardium. With the increasing use of thrombolytic therapy and coronary angioplasty, the indications for myocardial perfusion imaging are likely to expand. Gating of the cardiac chambers using radiolabelled red blood cells, on the other hand, will meet increasing competition from developments in dynamic CT and MRI which are superior for delineating myocardial wall motion although are less adaptable to exercise studies. It will also be possible to study wall motion routinely with technetium-99m MIBI when dynamic SPECT machines become more widely available. Gated tomography will be possible with these machines without the unduly long acquisition times currently required for conventional gated SPECT. Another novel myocardial imaging agent recently introduced is indium-Ill labelled antimyosin monoclonal antibody which gains access to and targets 417

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myosin following myocardial infarction (Khaw et al, 1987a,b). The clinical role of this agent remains unclear except in circumstances where the diagnosis of infarction is difficult to establish such as after coronary artery bypass surgery. More interesting agents for application to myocardial infarction will be technetium-99m labelled blood cells. P256, for example, is an antiplatelet antibody which recognizes the Ilb/IIIa fibrinogen receptor on primate platelets and is undergoing development as an agent for in vivo labelling of platelets (Peters et al, 1986; Stuttle et al, 1989). Deep vein thrombosis following total hip replacement can readily be imaged with indium-111 labelled P256. Thrombus appears more prominent wih this agent compared with conventionally (in vitro) labelled platelets because the blood background decreases more rapidly, giving a higher targetto-background ratio. With technetium-99m labelled P256, SPECT of the coronary circulation will be possible. Platelet involvement in acute myocardial infarction is the subject of intense current research. Platelets almost certainly aggregate at the site of the plaque fissure which precipitates acute coronary thrombosis. There is now evidence to suggest that timely thrombolysis results in reduced mortality in acute myocardial infarction, but that benefit is gained only in those patients with recent thrombosis (GISSI, 1987). No diagnostic test is currently available to identify these patients and this emphasizes the potential role of antiplatelet monoclonal antibodies. Platelets are also implicated in restenosis of coronary arteries, after coronary angioplasty and coronary artery bypass surgery, via the platelet-derived growth factor (Ross, 1986). Although this may be a more difficult area to study with labelled platelets their potential is self-evident. Acute myocardial infarction is followed by neutrophil infiltration around the infarcted myocardium. This has been clinically demonstrated with indium-Ill labelled leucocytes in the immediate post-infarction period (Bell et al, 1987), although their diagnostic value is limited. However, neutrophils are postulated to have a damaging effect on the myocardium, similar to their adverse effects on a wide variety of other tissues into which they migrate. Imaging and quantifying their migration into acutely infarcted myocardium may have prognostic implications as well as providing a useful clinical research tool. Technetium-99m labelled neutrophils and SPECT should give improved data in this area. A new radionuclide with application to nuclear cardiology is gold-195m, which is ultra-short-lived and generator-produced from mercury-197 (Caplin et al, 1986). Because of the high administered doses possible with short-lived radionuclides, first-pass data with high statistical accuracy are obtainable. It may also be possible to use this agent for the repeated measurement of blood flow to other organs such as the kidney. Such rapid sequential injections facilitate the study of physiological and pharmacological interventions. In cardiac studies, for example, dynamic exercise acquisition necessary for gated blood pool studies can be avoided; 418

this is an advantage in view of the movement errors associated with exercise. Important new radiopharmaceuticals for imaging the peripheral vascular system are the radiolabelled monoclonal antibodies to fibrin and to platelets; firstly, there is no need for autologous platelet separation; secondly, the monoclonal antibody can be labelled with a variety of radionuclides, including short-lived tracers such as iodine-123 and technetium-99m; and thirdly, the monoclonal antibody is cleared from blood faster than platelets so the blood background Tails more rapidly, promoting a better target-to-background ratio. Although P256 whole antibody is itself a platelet proaggregant, its monomeric fragment (Fab) is inert with respect to platelet function. Furthermore, because of its relatively small molecular size, the Fab fragment undergoes some clearance into the urinary tract, contributing to the faster blood clearance. In a preliminary investigation in our unit, indium-Ill labelled P256 has shown great promise for localizing deep vein thrombosis following total hip replacement (Fig. 4). Because the agent can be administered sequentially within a period of 10 days (the time required to mount a potential immune response), it can be used to study the natural history of deep vein thrombosis. For instance, we have shown in these patients that, contrary to current thinking, calf vein thrombus frequently embolizes. The indications for antifibrin monoclonal antibodies are generally similar to those of the antiplatelet monoclonal antibodies (Koblik et al, 1989). These monoclonal antibodies recognize an epitope on fibrin and do not cross react withfibrinogen(Rosebrough et al, 1988). Although they have some theoretical advantages over antiplatelet monoclonal antibodies, these have not yet been substantiated in clinical trials. Such advantages include the ability to image older thrombi, which are no longer accumulating platelets, and to image thrombus after the initiation of anticoagulant therapy, which is thought to inhibit platelet accumulation on to thrombus. Antiplatelet monoclonal antibodies, on the other hand, have a theoretical advantage on the arterial side of the circulation where platelet accumulation predominates over fibrin formation. Other novel agents for imaging deep vein thrombus are radiolabelled fragment El (Knight et al, 1985), a fragment of fibrin polymer which recombines with preformed fibrin in vivo, and technetium-99m HMPAO labelled platelets (Becker et al, 1989c). Mention has already been made of the possibility of imaging endothelium with monoclonal antibodies recognizing receptors expressed during inflammation. Other approaches to imaging abnormal vessels include radiolabelled low density lipoproteins (Sinzinger & Angelberger, 1988), fibronectin (Uehara et al, 1988), polyclonal immunoglobulin (Fischman et al, 1989) and methylenediphosphonate MDP (Lantto et al, 1989). An area of physiology which has been little exploited in nuclear medicine, but which may have some clinical relevance, is capillary permeability to small hydrophilic solutes. Radiolabelled proteins, either albumin or transThe British Journal of Radiology, June 1990


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(c) Figure 4. Positive indium-111 labelled P256 images in a patient who underwent total hip replacement 48 h previously. Courtesy of Mr A. W. J. Stuttle. (a) Posterior images of the legs, showing uptake in the right propliteal fossa (knee marker arrowed), (b) Anterior image over chest, showing abnormal activity in region of right main pulmonary artery, (c) Ventilation (krypton-81m)/ perfusion (technetium-99m MAA) scintigraphy, showing mismatched perfusion defects in upper and lower lobes of the right lung.

ferrin, have been used to quantify protein leakage through the microvasculature, particularly in the lung in the adult respiratory distress syndrome (Rocker et al, 1989). However, a leak to proteins presumably represents severe capillary disruption. Conventional radiopharmaceuticals, like technetium-99m DTPA or radiohalides, could therefore be useful in the detection of more subtle abnormalities of capillary endothelium, Vol. 63, No. 750

and a simple approach to measuring the transfer of small solutes from the intravascular to the extravascular space has recently been described (Peters & Myers, 1989). Oncology

A number of radiopharmaceuticals are used in a nonspecific way to image neoplasms, including gallium-67 419

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and thallium-201. Technetium-99m HMPAO has recently been used in a similar way, with encouraging results (Rowell et al, 1989). Metaiodobenzylguanidine (MIBG), on the other hand, specifically targets neuroendocrine tumours as a result of uptake into sympathetic neurosecretory granules. MIBG, which is an analogue of guanethidine, was developed to image phaeochromocytoma and, labelled with iodine-123, remains the best radiopharmaceutical for this purpose. It is becoming increasingly used for the detection and staging of neuroblastoma (Hoefnagel et al, 1987) although its precise role in this disease in comparison with CT, MRI and conventional bone scintigraphy remains to be established. The main thrust in oncological nuclear medicine has been the development of radiolabelled monoclonal antibodies which recognize tumour-specific antigens (Epenetos, 1988). Over the last few years there has been a proliferation of such monoclonal antibodies and their intended uses. Serious fundamental problems remain to be solved and leave the technique, at its present stage, with an unproved clinical role (Pauwels & Van Kroonenburgh, 1988). These problems include heterogeneity of antigenic expression in tumours, antigenic modulation, suboptimal antigen specificity for tumour cells resulting in cross-reactivity with normal host cells, and, because of molecular size, limited access to tumour antigens. The high blood background common to most radiolabelled proteins also reduces target-to-background ratio. This has resulted in the use of antibody fragments, which, because of their smaller molecular size and more rapid clearance from blood, give a higher target-to-background ratio, and, more recently, the exploitation of the very strong affinity between streptavidin and biotin. A few days following injection of cold monoclonal antibody conjugated with streptavidin, radiolabelled biotin is injected and this targets the streptavidin-monoclonal antibody complex which by then is fixed to the tumour antigen. Biotin remaining unbound to its streptavidin target is cleared rapidly through the urinary tract leaving a low background against which to visualize biotin that has combined with streptavidin. Various other permutations are possible. Thus, cold biotinylated monoclonal antibody can be given followed by radiolabelled streptavidin. Although streptavidin is a large molecule, it has a fast clearance from blood. Alternatively, radiolabelled monoclonal antibody-streptavidin complex can be "chased", sometime after injection, with cold biotin. This combines with circulating streptavidin-antibody complex, resulting in the formation of macromolecules, which, because of their size, are rapidly cleared by the reticulo-endothelial system. This, in other words, represents an attempt to clear the circulating background activity. Unfortunately, the biotinavidin approach, although giving promising results in the experimental animal, has not yet been shown to work for human tumours. The human cancers most extensively studied with radiolabelled monoclonal antibodies include carcinomas of the colon, ovary and breast, melanoma and the germ 420

cell tumours (seminoma and teratoma). In order to make effective use of radiolabelled monoclonal antibodies in the diagnosis of primary disease, they must be combined with sensitive, simple screening techniques. Furthermore, they will have more clinical value if there are no alternative non-invasive techniques for diagnosis. An example is carcinoma of the ovary, which, in a wellwoman clinic, is excluded by clinical and ultrasound examination in the overwhelming majority of patients. When abnormalities are found, however, the next investigation is likely to be invasive, such as laparoscopy or laparotomy. The role of monoclonal antibodies in the detection of primary or secondary disease in the symptomatic patient at presentation is unclear. They may have a use in circumstances which present difficulties for conventional imaging, such as detection of lymph node deposits in carcinoma of the breast, intra-abdominal deposits from carcinoma of the colon and retroperitoneal spread from cervical cancer. Since there should be a therapeutic option, monoclonal antibodies for detecting secondary melanoma have a doubtful role. The third setting in which radiolabelled monoclonal antibodies may have a role is recurrence. Ovarian cancer again provides an example. Thus a positive monoclonal antibody scan may deter a "second-look" laparotomy (Granowska et al, 1988), which is usually indicated in patients with stage III disease following chemotherapy. Although, at present, the overall place of radiolabelled monoclonal antibodies in oncological diagnosis is uncertain, intense research efforts in thisfield,and the intrinsic attraction of the technique, may modify this situation. Paediatrics

The main development in paediatric nuclear medicine will simply be its wider use in child care (Carty, 1988). Modern radiopharmaceuticals are not the radiotoxic compounds that they are imagined to be for paediatric administration. Thus many intravenous urograms should be replaced by renography and DMSA scanning, micturating cystourethrograms by indirect isotope cystography, and skeletal surveys by bone scans. Paediatric nuclear medicine differs from adult nuclear medicine in four respects: firstly, patient handling, which critically determines the quality of paediatric radionuclide images; secondly, developmental aspects of paediatric physiology, such as neonatal transitional nephrology; thirdly, the spectrum of diseases encountered, with a higher incidence of congenital abnormalities and lower incidence of degenerative conditions; and fourthly, technical factors, such as the greater use of magnified views, pin-hole collimation and different specification requirements of gamma cameras purchased for paediatric use. Children are not just small adults. During the neonatal period, for example, relative glomerular filtration rate and renal blood flow are considerably less than adult values and continue to increase until at least 2 years of age. Relative extracellular fluid volume is much The British Journal of Radiology, June 1990

Recent advances and future projections in clinical radionucUde imaging

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Figure 5. Indirect radionuclide cystography using technetium- 99m labelled MAG 3. (a) Posterior images immediately before and after micturition (performed 20 min after injection of MAG 3), showing bilateral vesico-ureteric reflux, worse on the right, (b) Time activity curves over both kidneys and bladder, (c) Print-out of urodynamic data. Courtesy of Dr H. Gatanash.

greater in the neonate, and relative renal tubular length shorter. These factors combine to create a situation analogous to chronic renal failure in the adult, and give rise to a technetium-99m DTPA renogram with an early peak and "flat" third phase. From this example it should be evident how nuclear medicine techniques can contribute to our understanding of neonatal and developmental physiology. A number of developments in nuclear medicine have particular relevance to paediatric nuclear medicine. Vol. 63, No. 750

Whereas, in the adult, the most frequently performed examination is the bone scan, in paediatrics it is renal imaging. MAG-3 should, therefore, make a big impact in paediatric nuclear medicine. Because of its higher renal extraction efficiency and more rapid clearance from plasma compared with DTPA, MAG-3 may be particularly useful for imaging the immature neonatal kidney, for the older child with obstructive or dilatational uropathy, such as in posterior urethral valves and prune-belly syndrome, and for indirect isotope cysto421

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graphy, the quality of which depends on the rate at which radioactivity is transferred from the upper tracts to the bladder (Fig. 5). Another new radiopharmaceutical with paediatric applications is technetium-99m HMPAO, for both white cell scanning and brain imaging. Paediatricians have shown some reluctance to use indium-Ill labelled white cells because of the high doses to bone marrow and spleen, and so the technetium-99m complex is greatly welcomed. The increasing recognition of the association between renovascular disease and cerebrovascular disease is resulting in an increased use of technetium-99m HMPAO for assessing cerebral perfusion. Whereas adult nuclear physicians perform V/Q lung scanning almost exclusively for the diagnosis of pulmonary embolism, paediatric nuclear physicians have recognized its use in a variety of other lung disorders such as asthma, congenital lobar emphysema, sequestrated segments, the follow-up of lung dysfunction in kyphoscoliosis, the follow-up of inhaled foreign body, bronchiectesis and the small lung. V/Q scanning in congenital lobar emphysema has demonstrated the intermittent nature of the bronchial obstruction (Peters et al, 1989) and reassured surgeons pursuing conservation management. V/Q lung scanning has also been useful for investigating paediatric pulmonary physiology. For example, it has demonstrated important differences between adults and children with respect to the ventilation and perfusion gravitational gradients. Thus, whereas perfusion in children shows the same gravitational distribution as in adults, the ventilation gradient is reversed, with ventilation being less in the dependent regions (Bhuyan et al, 1989). This has important therapeutic implications in patients with unilateral lung disease, in whom it has been shown that the circulating pO2 increases when the patient is nursed in the lateral decubitus position with the good lung uppermost (Cohen et al, 1984). Finally, ultra-short-lived generator-produced radionuclides are obviously attractive for paediatric cardiology and blood flow studies. Krypton-81m, by intravenous infusion in dextrose solution, is one such radionuclide that has been exploited in paediatric nuclear medicine, for studies of right ventricular function or oesophageal function, but on a rather small scale. Brain

Brain imaging almost disappeared completely from most nuclear medicine departments when CT became established, having previously been performed with pertechnetate, technetium-99m DTPA or technetium99m glucoheptonate, all of which are unable to cross the normal blood brain barrier. The introduction of technetium-99m HMPAO has resulted in a renewed interest in radionuclide brain imaging, although the diagnostic role of this tracer remains to be clearly defined (Ell, 1987). PET studies of the brain have occupied a major fraction of PET time and technetium-99m SPECT HMPAO is largely seen as a limited substitute for PET, but with wider availability (Anonymous, 1989). 422

Technetium-99m HMPAO is a lipophilic complex, which, after intravenous injection, is rapidly extracted by tissues broadly in proportion to their fraction of cardiac output. Insofar as the amount of activity deposited in an organ is proportional to the fraction of cardiac output it receives, it is necessary for that organ's extraction to be equal to mean whole body extraction fraction, rather than for it to be 100% (Sapirstein, 1958). Because technetium-99m HMPAO extraction fraction is considerably less than 100% with respect to the whole body, technetium-99m HMPAO behaves more like potassium than like a microsphere (notwithstanding the low extraction fraction of the brain for potassium). Blood clearance is therefore very rapid. Once inside cells, technetium-99m HMPAO is converted to secondary species which are hydrophilic and therefore unable to leave the cells. The distribution of activity, therefore, remains stable for some hours after injection. This is useful because regional cerebral blood flow is determined by the distribution of HMPAO at the time of injection, rather like regional pulmonary blood flow is recorded at the time of injection of labelled microspheres. In other words, the distribution of blood flow is "frozen" at the time of injection. PET remains a powerful tool for the functional investigation of the brain with the ability to measure cerebral blood flow using carbon dioxide labelled with carbon-11, cerebral oxygen utilization using oxygen-15, cerebral glucose utilization using fluorine-18 labelled deoxyglucose and cerebral blood volume using carbon11 labelled carbon monoxide, which labels red cells. These parameters can be measured using steady state techniques or from kinetics analysis. Measurement of cerebral blood flow by PET is of interest because technetium-99m HMPAO attempts to reproduce it and because it is analogous to the measurement of regional pulmonary ventilation with krypton-81m. Thus, the decay constant of oxygen-15 is rapid enough (with a half-time of 2 min) to be comparable with the rate of wash-out from the brain of labelled water, to which carbon dioxide is converted in the lung following inhalation. An equilibrium is therefore established between inflow rate (which can be measured from arterial blood sampling) and removal rate, which is determined by wash-out rate of labelled water (related to cerebral perfusion) and isotope decay rate (which is known). Although PET of the brain has much greater research potential than technetium-99m HMPAO brain SPECT, their clinical indications are broadly similar and are summarized as follows. (a) Cerebrovascular disease. Technetium-99m HMPAO has a potential role in the diagnosis of focal cerebral ischaemia (De Roo et al, 1989). The major challenge is the identification of viable brain tissue following stroke, as a guide to the use of thrombolytic therapy. Because of the rapid onset of brain infarction after stroke, measurable in minutes (in contrast to hours in the myocardium following coronary occlusion), intervention is aimed at salvage of cerebral tissue which is at The British Journal of Radiology, June 1990


risk. Correlative studies with PET may focus this role because of the latter's capacity to measure additional parameters, such as the oxygen extraction ratio (which is elevated in ischaemic brain but subnormal in tissue going on to infarction), the cerebral metabolic rate for oxygen (CMRO2) (the zone of which, showing a reduced level, is larger than the apparent volume of infarction demonstrable on CT), and the ratio of cerebral metabolic rates for oxygen and glucose (which falls in ischaemic brain as a result of anaerobic glycolysis). Technetium-99m HMPAO is normally stable within cells for a number of hours after injection. A parameter of viability that has recently been suggested is the rate of tracer wash-out (Costa & Ell, 1989), and it will be interesting to correlate this with the physiological variables defined by PET. (b) Dementia. Using PET, relatively specific regional patterns of decreased cerebral flow and CMRO2 have been described in various forms of dementia. In Alzheimer's disease, for instance, there is decreased flow and metabolism involving the posterior temporal and Figure 6. Technetium-99m HMPAO brain SPECT in a patient parietal cortices, extending, with more advanced with temporal lobe epilepsy, performed in the interictal period. disease, to involve the frontal cortex and correlating There is reduced uptake, indicating reduced perfusion, in the with clinical assessments of the degree of dementia. temporal lobe on the left. Courtesy of Dr D. J. Wyper. Similar distributions have been described in Parkinson's disease and Creutzfeld-Jacob disease. Pick's disease and Steele-Richardson syndrome, however, are associated with focal frontal hypoperfusion and hypometa- epilepsy have been based on carbon-11 labelled opiate bolism. In Huntington's disease the changes are more receptor ligands. Further clinical applications being explored for techdiffuse, may antedate the chorea and could, therefore, act as a marker for subclinical disease. In multi-infarct netium-99m HMPAO include psychiatric disease, dementia, focal reductions in cerebral blood flow and Parkinson's disease, cerebral trauma and migraine. In CMRO2 are randomly distributed. Technetium-99m general, information frequently not apparent on CT and HMPAO SPECT studies largely reflect these PET MRI is gathered from technetium-99m HMPAO changes, and, although studies orientated towards SPECT, but the interpretation of this information is not clinical research are better performed with PET, techne- clear. tium-99m HMPAO SPECT widens the diagnostic scope of nuclear medicine departments without PET. For Receptor labelling in the brain Imaging neurotransmitter receptors in the central example, technetium-99m HMPAO SPECT has a potential role in the categorization of demented patients nervous system is a new and exciting technique exemplifying the approach to in-vivo receptor/ligand kinetics with a view to prognostication (Neary et al, 1987). which is available with PET technology. With quantitative imaging it is possible to determine, by Scatchard (c) Epilepsy. Technetium-99m HMPAO has a diag- analysis, the affinity of carbon-11 labelled ligands for nostic role which is more clearly defined in partial their receptors, and the number of the latter available (temporal lobe) epilepsy than in its other applications. for binding. An example is the use of carbon-11 labelled Thus the demonstration of hypoperfusion in one or the spiperone, which has affinity for dopamine receptors other temporal lobe (Fig. 6) is likely to be of value in (Wagner, 1988). The prospects offered by these PET planning surgical intervention, in contrast to CT (and, studies have stimulated work with single-photon emitto a lesser extent, MRI) from which it is difficult to ters and SPECT, which would be available on a wider localize the epileptogenic focus. Ictal hyperperfusion scale. An early example is the labelling of benzodiazeand interictal hypoperfusion have been observed with pine receptors with iodine-123 labelled flumazenil, a PET and have functional correlates with abnormalities benzodiazepine receptor antagonist (Ell, unpublished). in CMRO2 and CMRglu, demonstrable with PET. Interesting cerebral metabolic data in epilepsy have also Metabolic endocrine been recorded in relation to the effects of, and withImaging the thyroid gland with radioiodine is the drawal from, anticonvulsant therapy. Furthermore, earliest example of using a labelled metabolic intermerecent approaches to investigating the pathogenesis of diary to image an organ. Later and more sophisticated Vol. 63, No. 750

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examples are MIBG, radiolabelled cholesterol analogues (for imaging the adrenal cortex) and the positron emitter,fluorine-18labelled deoxyglucose (which marks glucose utilization). These are compounds "tailormade" for a specific purpose, with pharmacokinetics that are well understood. MIBG, for example, is an analogue of noradrenaline and is taken up into sympathomimetic amine stores, including adrenergic nerve endings and the adrenal medulla. Although MIBG is avidly taken up by tissues rich in adrenergic nerve endings, such as the myocardium and salivary glands, its main purpose is to image phaeochromocytoma and other neuro-endocrine tumours. More recent examples of this approach are the labelling of serum amyloid protein (SAP) for imaging amyloid deposits and radiolabelled somatostatin analogues for imaging endocrine-related tumours expressing somatostatin receptors. It has recently been demonstrated in amyloidosis that SAP, a normal plasma protein, targets amyloid deposits (Hawkins et al, 1989). Iodine-123 labelled SAP, injected intravenously, is able to localize amyloid deposits of AA (secondary) and AL (primary) amyloidosis and the periarticular amyloidosis associated with haemodialysis

(Fig. 7). High resolution imaging can show uptake in the adrenal gland, myocardium and carpal bones (Fig. 8) in addition to obvious deposits in liver, spleen, kidney and bone marrow. Imaging the amyloid deposits in the brain associated with Alzheimer's disease is the next challenge facing this technique. Pharmacokinetic studies are also interesting. Thus, whereas the half-time of clearance from plasma in normal subjects is 31 h, it falls to about 30 min in patients with extensive hepatic amyloid. Elimination from the body, however, is slower in patients with amyloid, reflecting a greatly reduced catabolic rate of labelled SAP after uptake into amyloid deposits. Imaging endocrine related tumours with an iodine123 labelled somatostatin analogue is an example of the ingenious manipulation of a naturally occurring biological agent for localizing specific disease (Krenning et al, 1989). Somatostatin is a peptide synthesized in a variety of tissues including the central nervous system (where it is probably a neurotransmitter), the gastro-intestinal tract and pancreas. Although it has a spectrum of functions, it generally behaves as an antiproliferative and antisecretory agent. It also inhibits the effects of gastrin, insulin and glucagon, hence its therapeutic role in gastrinomas and insulinomas. These neoplasms and

Scr t

(a) (b) Figure 7. Whole body images acquired 24 h after injection of iodine-123 labelled serum amyloid component P (SAP). Courtesy of Dr P. N. Hawkins, (a) Normal subject, showing predominantly a blood pool signal with evidence of free radioiodine (posterior left, anterior right), (b) A patient with amyloid deposits involving the spleen, both kidneys and right adrenal gland (left adrenal gland not visible) (posterior right, anterior left).

424



(a)

(b)

Figure 8. Spot views over wrists following iodine-123 SAP in: (a) a normal subject and (b) a patient, on long-term haemodialysis, with carpal tunnel syndrome. Courtesy of Dr P. N. Hawkins.

others, including carcinoid and meningioma, express somatostatin receptors. Hormone secreting tumours that are positive on scintigraphy with iodine-123 labelled somatostatin analogue show a decrease in hormone secretion in response to subcutaneous administration of cold analogue, whereas tumours negative on scintigraphy show no response, suggesting that they possess no receptors. The corollary of this is that scintigraphy may have a role in predicting the response to somatostatin treatment of those tumours lacking a specific hormonal marker. These last two approaches represent important prototypes and indicate the directions in which nuclear medicine is developing, i.e. with greater emphasis on complex labels and the expertise in cell biology and immunology required to develop them.

(20min), oxygen-15 (2min) and nitrogen-13 (lOmin), the radiochemistry laboratory must be on-line between the cyclotron and the PET camera. PET gives highdefinition, three-dimensional images. The PET camera consists of a ring of hundreds of detectors, two of which simultaneously detect the two anihilation photons associated with each positron emission. Since these photons are emitted at 180° to each other (i.e. in opposite directions), the point of origin of the positron can be accurately localized in three dimensions. Anihilation photons are emitted with the same energy, 511 keV, whatever the positron-emitting source. This greatly simplifies the use of multiple tracers such as in cerebral blood flow and metabolic studies using labelled water, oxygen and deoxyglucose. Most of the positron emitters are short-lived which, although giving rise to one set of complexities, also facilitates the use of multiple tracers. Positron emission tomography The challenge currently facing nuclear medicine with At present, because of its expense, positron emission respect to PET is to expand its availability beyond those tomography (PET) is limited to a few centres. The value large centres equipped to run it comprehensively. First, of PET is based on the availability of positron-emitting PET machines will have to be cheaper. One way of radionuclides of carbon-11, oxygen-15 and nitrogen-13, achieving this, at the expense of reduced sensitivity, is to which can be utilized for imaging metabolism, blood replace the complete ring of detectors with segments flow and oxygen utilization (Ott, 1989). In addition, that have rotational capability and that could be glucose can be labelled as deoxyglucose with fluorine-18 purchased piecemeal. Second, the positron emitters in which form it becomes metabolically trapped and can must be made available on a wider scale. This would be therefore be used for imaging glucose utilization. achieved by the use of generator-produced radionuclides Carbon-11 can be incorporated into a great number of such as gallium-68 and rubidium-82, or by the shipmetabolic intermediaries and pharmacological ment of longer-lived radionuclides, such as fluorine-18 compounds, emnphasizing the enormous potential of and gallium-68, or by the purchase of a "baby" cyclothis imaging modality. This also underlines the expense tron. Baby cyclotrons are relatively inexpensive, and, involved since, owing to short half-lives of carbon-11 although able to produce oxygen-15, carbon-11 and Vol. 63, No. 750

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nitrogen-13, the cost of the radiochemical personnel required to process the tracers puts this approach beyond most budgets, particularly if it is proposed to incorporate carbon-11 into metabolic intermediaries. Nonetheless, when one considers the enormous scope in diagnostic imaging and clinical research, PET must represent an enormous horizon in nuclear medicine. The pharmaceutical companies are begining to realize the contribution PET could make in clinical pharmacology, following the pioneering work on the labelling of neurotransmitter receptors in the human brain with radiolabelled narcoleptics, and on the labelling of beta adrenergic receptors in the lung.

cylindrical crystal which will detect photons emitted from the source in 360°. These do exist but the cost limitations are self-evident. Improvements in computer software will encompass a number of philosophies, including the interface with the user ("user friendly" systems) and the provision of easier programming. SPECT will become truly quantitative, i.e. in absolute terms in which count rate per "voxel" will represent a fraction of the injected dose rather than, currently, in relative terms. Finally, the concept of networking will be advanced in which it will be possible to correlate, on the same video screen, nuclear medicine images with those generated by other modalities such as CT, MRI and PET.

Physics

Positron emission tomography has already been discussed. Technical developments in single-photon detection can be considered under three headings: new radionuclides, camera design and computers. Developments in radionuclides will to some extent be linked with developments in camera design. A promising new ultra-short-lived radionuclide is iridium-191m. This has a half-life of 5 s, a satisfactory photon energy and is produced from an osmium-191 generator which has a useful shelf life of about 3 weeks. Its clinical value in nuclear cardiology has recently been explored (Franken et al, 1989). New camera design, using thick as opposed to ultrathin crystals, would permit the exploitation of radionuclides which, if it were not for their high photon energy, could be very useful, for example indium-113m and gallium-67. Such thick crystals would be combined with position sensitive photomultipliers capable of locating this information in three dimensions in contrast to two with conventional thin crystals. This permits a departure from the usual trade-off between resolution and sensitivity. Nonetheless, inherent limitations in resolution will remain, more as a result of collimator limitations than of intrinsic resolution of the camera itself (crystal and photomultiplier tube assembly). In other words, the trade-off of sensitivity against resolution at the level of the collimator is unlikely to improve. Analogue cameras are being replaced by digital cameras, which offer automatic correction for various causes of non-linearity and non-uniformity, and facilities for simultaneous dual energy acquisition (which is very useful, for example in V/Q lung scanning), for image manipulation, such as zooming, and for avoidance of common simple technical errors. Other improvements will include lighter mobile gamma cameras and bigger fields of view. SPECT is becoming increasingly important in an age of three-dimensional imaging. SPECT is facilitated by double-headed cameras. Extending this concept to multiple-headed cameras will permit dynamic SPECT, i.e. the facility to acquire threedimensional images in rapid dynamic sequence. This is an important development if functional imaging with radionuclides is to keep pace with dynamic CT and MRI. It will also facilitate gated tomography, which, with a single rotating head, is currently too time consuming. An even better approach would be to use a 426

Other systems

Advances are also being made in haematology, gastroenterology and bone imaging. An interesting application of an old test in gastroenterology, for instance, is the use of carbon-14 labelled urea by mouth to diagnose Campylobacter pylori as a cause of gastritis and peptic ulceration (Lewington & Ackery, 1989). The organism elaborates urease which hydrolyses the labelled urea. Elevated levels of labelled carbon dioxide in expired gas indicates infestation. Dimethylamino diphosphonate (DMAD) is a new bone agent which has a relatively low uptake in normal bone compared with MDP but a higher target-to-background ratio in abnormal bone. This improves lesion detectability at a cost of more difficult anatomical localization (Coleman et al, 1989). Conclusion

Nuclear medicine is currently experiencing major developments in radiopharmaceuticals on three main fronts: firstly, new technetium-99m labelled agents for the replacement of a number of established agents; secondly, complex biological agents for novel imaging applications; and thirdly, a proliferation of new compounds for labelling with positron emitters. New SPECT machines and a wider availability of clinical PET imaging will complement these developments. Over the next 5 years we will, as a result, see great strides in functional imaging. Acknowledgments I am grateful to the following for helpful discussions and guidance: Professor J. P. Lavender, Drs I. Gordon, M. J. Myers, T. Jones, R. S. J. Frackowiak, A. Todd-Pokropek, V. R. McCready, J. F. Cleland, A. A. Epenetos and J. M. B. Hughes. Pamela York typed the manuscript, cheerfully. References AL-NAHHAS, A. M., MARCUS, A. J., BOMANJI, J., NIMMON, C.

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