Professor George Taplin’s group at UCLA were instrumental in recognising the importance of V/Q imaging and promoting its use with both ¹³³Xe (an inert radioactive gas and a by-product of the uranium fission process) and ^99mTc-based aerosols as the ventilation agents. Despite an extensive range of protocols developed over the years, ¹³³Xe is far from suitable as a ventilation imaging agent because of its high radiation dose and a gamma emission energy (81keV), too low for good spatial resolution. All the aerosol agents produced by one type of nebuliser or another, were highly inefficient in terms of time taken to administer a reasonable dose, and their lung penetration was often compromised by airways obstruction, leading to almost complete trapping in the central airways in the significant proportion of patients thus afflicted.
An invited lecture from (the now late) Professor George Taplin at the first Asia and Oceania Congress of Nuclear Medicine in Sydney, September 1976 “Lung imaging in pulmonary disease” in effect highlighted the mismatch between the quality of the perfusion agent and the different ventilation agents, and led to our search for a better ventilation tool that was truly congruent with its perfusion counterpart.

At first, the challenge was to try and make nebulised particles as small as possible. The need to do this had been proven by Friedlander in his book “Dust, Mists Smoke and Haze”(1), where he had performed a “Meta-analysis” of all the data on inhaled particles from the world literature. From fundamental physics considerations it was clear that the smallest aqueous aerosols formed from nebulisation via a “Collison atomiser” were ~ 0.5µ diameter. However, water vapour in the conducting airways leads to supersaturation beyond about the 3rd of 23 divisions of the bronchial tree, and this in turn leads effectively to almost instant particle growth during inhalation. Pre-warming the solution in the nebuliser bowl to reduce particle size by lowering the surface tension and improve particle forming efficiency, and a settling chamber to remove larger droplets all help to some extent, but patients with obstructive disease still are not imaged satisfactorily. Thus it simply is not practical to form an aqueous aerosol that could transport to the alveolar region in the whole range of patients needing an examination.

At the time (1977), ^113mIndium chloride was being used as a blood label for identifying placental mislocation in pregnant women (placenta praevia). Indium volatilises at around 400ºC. A small amount of the active liquid was dried onto the end of a cigarette which was lit and a few draws inhaled. The resultant lung image, despite the low activity and poor resolution from the high energy gamma ray emitted (392keV), showed good even lung distribution. However, Indium use was being phased out with the advent of ultrasound imaging and it was felt pointless to pursue this radionuclide solely for lung ventilation work.
After initial attempts to develop a ^99mTc-labelled alcohol-based metered dose system from the current asthma inhaler technology also failed, the idea of igniting this aerosol to form carbon dioxide and water vapour was conceived. It proved to be highly effective, generating a monodispersed aerosol of 0.12µ diameter. The process was patented by the then local Health Commission in Canberra, and the agent was named “Pseudogas”. The firm of IJ&LA Tetley Pty Ltd (Tetley) was contracted by the Health Commission to work with the Inventor to make a commercially viable product(2). During development of the pre-production prototype, a laboratory version was used to examine 150 patients at Royal Canberra Hospital. By the time a reliably working prototype had been made, ^81mKr gas from a special cyclotron-produced generator was in use at the Hammersmith Hospital, London. ^81mKr with its 13 second half-life had become recognised as the “gold standard” for ventilation although the cost of production and the short half-life of its parent, ⁸¹Rb, precluded it ever having widespread acceptance as a continuously available imaging agent to satisfy the urgency demand of PE diagnosis.
A Pseudogas generator was transported to London and over three weeks, ventilation images were compared with ^81mKr ventilation in 10 in-patients with end-stage respiratory disease and 4 normal subjects(3). It was immediately obvious that in severe respiratory disease, Pseudogas still did not penetrate beyond points of obstruction, although it reflected the ventilation profile of these very sick patients rather better than the pure gas. Commercial development was suspended late in 1983 although Pseudogas continued in clinical use in Canberra hospital as it was so much better than conventional aerosols.
TECHNEGAS
From the realisation that tungsten in an inert gas was sustainably held at ~3000ºC in a standard incandescent lamp - well above the melting point for Technetium (2178ºC) – an attempt was made to emulate the original indium agent and vaporise ^99mTc or one of its salts with direct heating in an inert gas. The initial successful experiment used a 12volt tail light lamp from a motor vehicle on the filament of which had been dried some standard ^99mTc generator eluent. Attempts to scale this up to a practical apparatus were frustrated until it was recognised that the mode of action required a fine coating of tungsten oxide over the metal as a carrier for the activity. This in turn led to recognition that metal salts volatilised at lower temperatures than the pure metals.
In parallel with this, Tetley was asked to produce an apparatus capable of heating graphite crucibles to 3000°C and thus eliminate the possible concern from inhalation of tungsten oxide. Following a series of experiments over a period of months, it was surprisingly discovered that almost all the ^99mTc adsorbed on the surface of a graphite crucible simultaneously volatilised and became coated with graphite above 2200ºC.
Thus Technegas was created.
There was an inconsistency in the scientific rationale behind the mechanism, and for a time, after the announcement of the discovery of “Buckminsterfullerene”, it was felt we had in fact pre-dated the discovery and that Technegas was actually a “Fullerene” encapsulating ^99mTc. This presumption was enhanced by electron microscopic visualisation of carbon ‘cages’ in a Technegas sample deposited on an e.m. grid, and a mass spectrometer profile showed an entire family of Fullerenes present in Technegas. Most importantly though, none of the spectral peaks coincided with an additional 99 mass units as would be observed if a ^99mTc atom was trapped in a carbon cage.
It was in fact another 10 years before one of our group, Rod Browitt, finally unravelled the elegant mechanism behind Technegas production, highlighting just how serendipitous was the original discovery. The alternating current spikes of the heating circuit strike an arc in the intense thermal plasma of the inside of the crucible, etching off the ^99mTc metal simultaneously with carbon atoms. He and Prof. Tim Senden then observed that in a “thermopause” region above the crucible, the metal atoms coalesce and are simultaneously coated with intercalating hexagons of carbon to present only a pure graphitic surface to the environment.
Tetley took out a patent on behalf of the then ACT Health Commission, and immediate plans for commercial machine production were laid. In the meantime a research model unit was built and patient studies commenced within a few months of the original discovery.
A Federal Government agency introduced Amersham PLC of the UK to the technology, and they took out a marketing option with the Tetley company. They also assisted in designing a clinical trial comparing Technegas with ¹³³Xe in the diagnosis of PE with the view of using the data to create a file for approval for Technegas in the USA. Prototype units were built and sent to their Laboratories near London where they began to evaluate the agent, and recommend modifications to suit the market. At the time there were no regulatory requirements in Europe for “Devices” and Amersham began preparing for a European marketing exercise.
The first clinical studies were presented at the Australian meeting in Hobart in the presence of senior Amersham executives in April 1986. This led to an invitation from Amersham for a Clinician and the Inventor to travel to Goslar in Northern Germany later in the year for the European Nuclear Medicine meeting to present Technegas. Not long after this successful presentation, Tetley decided that Amersham were demanding too many modifications to the machine making it uneconomical to build, and his company terminated the agreement with Amersham. Tetley then went on to seek its own distributors for Europe.
PERTECHNEGAS
By early 1987, machines were being sold throughout Australia and much clinical data accumulated. As confidence in the technology grew so did the quality of the reports back to the referring doctors. This in turn boosted the referring clinicians’ confidence and more requests began to flow into Nuclear Medicine for V/Q imaging for suspected PE. One particular machine in Brisbane was apparently causing problems in that patients were experiencing clearance of the radioactivity from the lungs and appearance in the thyroid. The problem was traced to a wrongly labelled argon gas cylinder that clearly contained oxygen. This raised the possibility of using the rate of clearance clinically as a measure of the permeability of the air-blood membrane in the lungs. For several years this had been done with a DTPA aerosol from a nebuliser and found to be a useful marker for interstitial lung disease. However, delivering the aerosol to a patient whose breathing was already compromised, is not easy or always successful.
Experiments with controlled mixtures of oxygen in argon showed that from about 0.5% upwards the clearance phenomenon was constant. Several years later it was proved that Tc₂O₇ was formed and this reverted to pertechnetate in contact with moisture in the lung. Mr. Doug Mackey from the Prince of Wales Hospital in Sydney suggested the name Pertechnegas and it was immediately adopted. The great value of Pertechnegas was that it could be inhaled even by persons with severe respiratory dysfunction in only a few breaths, leading to a clear-cut mono-exponential wash-out curve that reflected the membrane integrity.
Several centres in different parts of the world have studied Pertechnegas in patients with lung complications from HIV AIDS (pneumocystis pulmonare), radiation damaged lungs (pneumonitis), and a relatively rare but difficult disease to differentially diagnose, fibrosing alveolitis. It may well prove to have a useful role in other conditions such as smoke inhalation injuries and interest is still being shown.

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1 Friedlander SK, Smoke, Dust and Haze. Publ. Wiley 1977
2 Burch WM, Tetley IJ & Gras JL. Technetium-99m ‘Pseudogas’ for diagnostic studies in the lung. Clin Phys Physiol Meas 5: (2), 79-85; 1984.
3 Arnott RN, Burch WM, Orfanidou DG, Gwilliam ME, Aber VR, Hughes JMB. Distributions of an ultrafine 99mTc aerosol and 81mKr gas in human lungs compared using a gamma camera. Clin Phys Physiol Meas 7: (4), 345-359; 1986.