Radiopharmaceuticals
`
` Mattia Riondato and William C. Eckelman
`
` 4
`
`4.1
`
` Introduction
`
`for
`radiopharmaceuticals
` Radiotracers and
`Nuclear Medicine imaging with applications in
`neurology have been implemented for more than
`50 years, based on the research efforts of scien-
`tists in the academic world, hospitals, and indus-
`try. The fi rst described imaging applications in
`humans were pioneered in the early 1950s in the
`USA for the detection of intracranial lesions and
`for the assessment of regional cerebral blood
`fl ow. Images were obtained using conventional
`gamma cameras, after administering inert radio-
`active gases by inhalation or radioactive metal
`complexes by injection. These agents were not
`aimed to detect any specifi c mechanism or
`molecular target, but they were used in the
`research setting for describing pathophysiologi-
`cal processes.
` The strong efforts in radiochemistry, in addi-
`tion to the technological improvements of the
`tomographic detection systems, contributed to
`enforce the interest for this emerging technique,
`
` M. Riondato , PhD (*)
` Nuclear Medicine Department , S. Andrea Hospital ,
` La Spezia , Italy
` e-mail: mattia.riondato@asl5.liguria.it
`
` W. C. Eckelman
` Molecular Tracer LLC , Bethesda , MD 20814 , USA
`
`and the fi rst studies in a clinical setting were
`reported during the 1960–1970s. The potential
`impact to patient care boosted the need of new
`and more specifi c radiotracers. Thus, the devel-
`opment of new tracers for neuroimaging applica-
`tions turned from using radioactive salts and
`known chelating agents to the modern concept of
`molecular neuroimaging. This latter model is
`based on the specifi c interaction between the
`imaging agent and the molecular structure or
`cellular process of interest, such as receptors,
`enzymes, transporters, or metabolic pathways.
`The emitting radionuclides contained within the
`agent provide a signal that can create an image if
`associated with the proper imaging system. After
`four decades of hard work in radiochemistry,
`hundreds of radiotracers containing different
`single photon and positron emitter nuclides have
`been developed and applied to the most common
`imaging modalities for the evaluation of brain
`function, accomplishing clinical and investiga-
`tional requirements (Table 4.1 ). A number of
`them have been approved by authorities and are
`currently used in Nuclear Medicine departments
`by physicians for specifi c applications, showing a
`potential impact for direct patient care. The major
`clinical areas of application include cerebrovas-
`cular diseases, movement disorders, dementia,
`epilepsy, and brain tumors. Neuroimaging radio-
`tracers are also employed for the study of other
`mental disorders such as schizophrenia, addic-
`tion, depression, and anxiety.
`
`© Springer International Publishing Switzerland 2016
`A. Ciarmiello, L. Mansi (eds.), PET-CT and PET-MRI in Neurology,
`DOI 10.1007/978-3-319-31614-7_4
`
`31
`
`Petitioner GE Healthcare – Ex. 1014, p. 31
`
`

`

`32
`
`M. Riondato and W.C. Eckelman
`
` Table 4.1 Early PET and SPECT
`human brain studies
`
` Date
` 1955
` 1963
` 1964
` 1965
` 1967
` 1969
` 1975
` 1976
` 1977
`
` 1981
`
` 1983
`
` 1984
` 1985
`
` >1985
`
` PET
`
` [ 68 Ga]EDTA
` [ 15 O]Oxygen
` [ 15 O]Water
`
` [ 11 C]Methionine
` [ 18 F]FDG
` [ 11 C]Tryptophan
` [ 11 C]Valine
`
` N-[ 11 C]Methylspiperone
` [ 18 F]FDOPA
` [ 18 F]Cyclofoxy
` [ 11 C]Raclopride
` [ 11 C]Carfentanil
` [ 11 C]Flumazenil
` Many
`
` SPECT
` [ 85 Kr]Gas
` [ 133 Xe]Gas
` [ 99m ]TcO 4 −
`
` [ 123 I]Iodoantipyrine
`
` N-isopropyl-[ 123 I]
`Iodoamphetamine
`([ 123 I]IMP)
` [ 123 I]IQNB
`
` [ 99m Tc]HMPAO
`
` Many
`
` Unexpectedly, the expanded range of radio-
`tracers hasn’t been followed by a parallel intro-
`duction of radiopharmaceuticals, as tools for
`answering clinical needs. During the last decade,
`radiotracers in order to get approval for clinical
`use or marketing authorization have been facing
`implemented radiopharmaceutical requirements,
`similar to those that are broadly applied to all
`drugs. In particular, the increased awareness for
`the quality and safety of radiopharmaceuticals
`and the need for confi rmation that the diagnostic
`agent has to provide clinically useful information
`contributed to make a widespread use of new
`agents very challenging.
` Last but not least, the use of SPECT and PET
`neuroimaging is not restricted to the clinical or
`investigational fi eld in the hospital Nuclear
`Medicine departments. During the last decades,
`this imaging technique has gained attention in
`neuroscience for the excellent capability to gain
`insight into disease mechanisms, describing the
`kinetics of the radiotracers and measuring target
`reserves, such as enzymes or receptors. For this
`reason, the standard methodology developed to
`study normal and pathological processes has
`been extended to support drug discovery in the
`
`universities and in the pharmaceutical industry.
`Neuroimaging with carbon-11 and fl uorine-18
`PET radiotracers has become a routine procedure
`for the development of biomarkers for novel cen-
`tral nervous system therapeutics. Using a PET-
`specifi c radiotracer identical to a drug candidate,
`brain penetration and target occupancy measure-
`ments can be defi ned. The drug interaction with a
`specifi c brain target can also be studied by com-
`petition, if a suitable radiopharmaceutical for the
`same target is available. Such information may
`have a substantial impact in a go/no-go decision
`on a set of drug candidates before fi rst-in human
`studies and furthermore may produce a signifi -
`cant effect on the overall pipeline cost for drug
`development.
`
`4.2
`
` Brain SPECT and PET
`Radiotracers: A Journey
`More than 50 Years Long
`
` From a historical perspective, the use of radio-
`tracers for brain scanning began in the early
`1950s for the localization and identifi cation of
`tumor damage by Sweet and Brownell [ 1 – 3 ].
`
`Petitioner GE Healthcare – Ex. 1014, p. 32
`
`

`

`4 Radiopharmaceuticals
`
`33
`
`Several compounds incorporating radionuclides
`were synthesized in order to obtain stable agents
`with a low toxicity profi le. Among these, the
`most satisfactory have been the positron emitters
`arsenic-74 as arsenate, copper-64 as versenate,
`and mercury-203 as neohydrin [ 4 , 5 ]. These scan-
`ning agents were not required to have any spe-
`cifi c interaction; they were able to permeate
`across the disrupted blood–brain barrier (BBB),
`thus allowing a rudimental detection of the mem-
`brane integrity and the lesion extensions with
`camera-type systems. Despite the raising interest
`for the methodology, these long half-life radionu-
`clides displayed suboptimal characteristics for a
`clinical use. A few years later, driven by favor-
`able nuclear properties, a radionuclide generator,
`and known chemistry, the researcher’s attention
`shifted to the development of a suitable agent
`containing gallium-68 [ 6 ]. As a consequence of
`the available “ready to use” 68 Ga-EDTA (ethyl-
`enediaminetetraacetic acid) milked from the gen-
`erator, and the introduction of new positron
`scintillator cameras [ 7 , 8 ], hundreds of patients
`were investigated during the 1960s [ 9 , 10 ].
`Unfortunately, the enthusiastic consensus for
`gallium- 68 imaging faded away during the 1970s,
`mainly because of the restricted use of fi rst-
`generation 68 Ge/ 68 Ga generators and the parallel
`development of new emerging radionuclide trac-
`ers, such us single-photon emitters technetium-
`99m/iodine-123 and
`the positron emitting
`carbon-11/fl uorine-18.
` Since the dramatic change that occurred at
`Brookhaven National Laboratory in the late
`1950s for the availability of 99 Mo/ 99m Tc genera-
`tors, the radiometal technetium-99m opened a
`new era in Nuclear Medicine as well as in early
`neuroimaging [ 11 ]. The ideal nuclear properties,
`the easy availability from a generator, and the
`fl exible chemistry facilitated the introduction of
`this emerging radionuclide that is, at present, the
`most employed for Nuclear Medicine procedures
`worldwide. The fi rst agents 99m Tc-pertechnetate
`and 99m Tc-DTPA (diethylenetriaminopentaacetic
`acid), as well as other gamma emitters radiotrac-
`ers thallium-201 and gallium-67 citrate, were
`evaluated for pathologies with altered BBB due
`to tumors or traumas [ 12 – 14 ]. However, all these
`
`radiotracers had the relevant constraint that they
`could be employed in neurological disease just
`for the evaluation of an altered BBB.
` In the late 1950s, a few years later from the
`initial brain tumor scanning, Munck and Lassen
`pioneered the assessment of cerebral blood fl ow
`(CBF) by using inert radioactive gases, thus
`providing the basis for regional CBF functional
`imaging. Evaluation in human brains was per-
`formed by administrating trace amounts of
`krypton- 85 by inhalation or intravenous injec-
`tion in saline solution [ 15 , 16 ]. In the original
`methodology, blood samples were collected
`from bilateral jugular veins and counted, refl ect-
`ing the global blood fl ow and oxygen use. The
`further advance was the measurement of the
`regional cerebral perfusion achieved by placing
`detectors on the patient’s scalp, to determine
`radiotracer accumulation and clearance on a
`regional basis, thus opening the way for a more
`modern concept of CBF scanning using a nonin-
`vasive approach [ 17 , 18 ].
` In the 1960s, major improvements occurred
`using molecular [ 15 O]oxygen for regional oxygen
`extraction and perfusion assessments, also taking
`advantage of the increased performances of
`imaging systems due to the introduction of fi rst-
`generation Anger cameras [ 19 ]. Ter-Pogossian
`and Brownell evaluated the radiotracer kinetics
`after a single breath by means of a pair of detec-
`tors. However, the fi rst results were not satisfac-
`tory because of the diffi cult interpretation of the
`collected data [ 20 , 21 ]. Some years later, radioac-
`tivity administration was modifi ed by using con-
`tinuous [ 15 O]oxygen inhalation, producing a
`“steady-state” brain distribution dependent on
`perfusion and oxygen extraction, as well as the
`physical decay of
`the
`radioisotope
`[ 22 ].
`Nevertheless, this technique suffered for some
`important disadvantages such as a constant deliv-
`ery of the radioactive gas and a long-time scan
`during which, it is assumed, no change in physi-
`ological status occurs. A more practical and suit-
`able method for imaging was then introduced
`using an intravenous injection of [ 15 O]oxygen
`water instead of a labeled gas [ 23 ], becoming a
`standard procedure for rCBF assessment with
`PET. These methods have been used in clinical
`
`Petitioner GE Healthcare – Ex. 1014, p. 33
`
`

`

`34
`
`M. Riondato and W.C. Eckelman
`
`settings since the 1980s in several clinical condi-
`tions
`including strokes, brain
`tumors, and
`Parkinson’s disease [ 24 – 26 ]. Despite the fact that
`the early evaluations were much more qualitative
`than quantitative, these methodologies represent
`a milestone for neuroimaging because of the
`direct impact on patient healthcare.
` An alternative to PET radiopharmaceuticals for
`the rCBF measurement was developed during the
`1980s by the parallel and successfully investiga-
`tional studies with iodine-123 and technetium-
`99m. These efforts resulted in the development of
`perfusion agents able to overpass the normal BBB,
`such as [ 123 I]iodoantipyrine, [ 123 I]IMP (l-3-[ 123 I]-
`iodo-α-methyl-tyrosine), [ 99m Tc]HMPAO ([ 99m Tc]
`exametazime), and [ 99m Tc]ECD ([ 99m Tc]bicisate).
`Most of them have reached an established clinical
`use for the evaluation of various neurological dis-
`eases such as dementia, Alzheimer’s disease, epi-
`lepsy, stroke, and Parkinson’s disease [ 27 – 30 ].
` A fundamental advance for Nuclear Medicine
`applications was the application of fl uoro-18-
`deoxyglucose ([ 18 F]FDG) to image cerebral glu-
`cose metabolism in 1976, destined to become the
`most important PET tracer to this day with indi-
`cations for tumors and for identifi cation of foci of
`epileptic seizures [ 31 , 32 ]. [ 18 F]FDG, a glucose
`analog, is able to delineate the glucose metabo-
`lism, which is very active in the normal brain and
`often hyperreactive in tumors.
` The promising results using a radiotracer able
`to interact with substrates, in addition to the early
`quantitative imaging applications, confi rmed the
`full potential of this emerging technique in
`describing molecular processes on human brain
`in health and disease. A general enthusiasm and
`great expectation for the future were soon satis-
`fi ed by a rapid increase in the development of
`new radioactive molecules, typically including
`the positron emitters carbon-11 and fl uorine-18
`and single-photon emitters
`iodine-123 and
`technetium- 99m. The new generation of radio-
`tracers were designed for displaying affi nity for
`receptors, enzymes, or other biological structures
`thus defi ned as radioligands, for interacting with
`specifi c metabolic pathways or for reproducing
`the chemical structures of drugs incorporating a
`radionuclide with identical characteristics or with
`
`minimal modifi cations or at least retaining the
`key biochemistry. Among the expanded range of
`imaging molecules, the fi rst widespread applica-
`tions included the regional amino acid metabo-
`lism using native amino acids or derivatives
`labeled with carbon-11, like [ 11 C]methionine,
`leucine, and unnatural amino acids [ 33 – 35 ]. A
`few years later, fl uorine-18 dihydroxyphenylala-
`nine ([ 18 F]FDOPA), a dopamine synthesis path-
`way analog, and N-[ 11 C]methylspiperone, a
`radioligand for dopamine/serotonin receptors,
`were used to assess for the fi rst time the neuro-
`transmission function in humans [ 36 , 37 ]. The
`mid- to late 1980s were characterized by a con-
`tinuous introduction of new radioligands with
`major advances for the quantifi cation of dopa-
`mine receptor subtypes ([ 11 C]raclopride, [ 11 C]
`Schering-23390), dopamine transporters ([ 11 C]
`nomifensine), central benzodiazepine receptors
`([ 11 C]fl umazenil), peripheral benzodiazepine
`receptors ([ 11 C]PK11195), opioid receptor ago-
`nists and antagonists ([ 11 C]carfentanil and [ 11 C]
`diprenorphine) [ 38 – 44 ], as well as for the enzyme
`monoamine oxidase type B ([ 11 C]deprenyl) [ 45 ].
`A new fi eld of research appeared to be very aus-
`picious for more specifi c and useful clinical
`applications with PET chemistry imposing a
`dominate role in neuroimaging.
` Radiotracer expansion certainly benefi tted
`from an increased understanding of both physio-
`logical and pathological molecular processes, but
`the great effort of chemists, pharmacists, biolo-
`gists, physicists, and physicians was key to the
`progress. The infl ux of scientists from various
`fi elds allowed the discovery and validation of
`new radiopharmaceuticals to achieve a vast array
`of targeted radiotracers. This great evolution was
`also facilitated by the increased availability of
`supporting technologies and infrastructures such
`as generators, cyclotrons, SPECT and PET scan-
`ners, and chemistry laboratories. In addition, the
`notable improvements in radiochemistry, mainly
`in
`labeling strategies for rapidly
`labeling
` molecules with high specifi c activity starting
`from the most popular short-life PET radionu-
`clides, have boosted the design of new radiotrac-
`ers claiming the important role this discipline is
`playing in this fi eld.
`
`Petitioner GE Healthcare – Ex. 1014, p. 34
`
`

`

`4 Radiopharmaceuticals
`
`35
`
` During the 1990s, a progressive investigation
`focused on the improvement of the existing imag-
`ing, as well as in modulating and delineating neu-
`rotransmission systems other than dopaminergic
`and serotoninergic. [ 11 C]WAY-100635, [ 11 C]
`MDL-100907, and [ 11 C]McNeil-5652 were intro-
`duced, respectively, for a more selective evalua-
`tion of serotonin receptor subtypes 1a/2a
`distribution and for the SERT/5-HTT transport-
`ers [ 46 – 48 ]. Novel [ 11 C]NNC112, [ 11 C]FBL457,
`and [ 11 C]-β-CIT displayed high affi nities, respec-
`tively, for dopamine receptor subtypes 1 and 2/3
`and for dopamine transporters [ 49 – 51 ]. Beyond
`the dopaminergic/serotoninergic systems, new
`imaging agents were aimed at exploring acetyl-
`cholinesterase enzyme ([ 11 C]MP4A and [ 11 C]
`PMP) and nicotinic receptor reserves (2-[ 18 F]
`F-A85380), as well as vesicular monoamine
`transporter type 2 ([ 11 C]DTBZ) and ATP-binding
`cassette (ABC) transporters like P-glycoprotein
`([ 11 C]verapamil) [ 52 – 56 ].
` For many years, the development of target-
`specifi c agents has been strongly dominated by
`PET chemistry, given
`the relatively easy
`replacement of a carbon, an oxygen or nitrogen
`with a radioisotope conserving the original
`chemical structures. However, the major world-
`wide diffusion of SPECT scanners promoted
`the investigation for the development of agents
`containing a suitable single-photon emitter
`radionuclide. A number of radioiodinated trac-
`ers which bind CNS receptors were synthesized
`and introduced successfully as alternatives to
`PET tracers in clinical settings. Iodinated deriv-
`atives displayed excellent properties for the
`quantitative evaluation of the muscarinic ([ 123 I]
`IQNB, [ 123 I]iododexetimide), dopamine ([ 123 I]
`IBZM and [ 123 I]epidepride), and benzodiaze-
`pine ([ 123 I]iomazenil and [ 123 I]NNC-13-8241)
`receptor reserves and for dopamine/serotonin
`transporter function ([ 123 I]-β-CIT) [ 57 – 63 ].
`Because of the intrinsic diffi culties to incorpo-
`rate a radiometal such as technetium-99m into
`small molecules, able to pass the normal BBB
`and conserving the affi nity for a specifi c target,
`investigational studies were not as consistent as
`for the main PET tracers in neurology. The syn-
`thesis and evaluation of the fi rst [ 99m Tc]-labeled
`
`tropane analogs that display selective dopamine
`transporter binding were reported in 1996 and
`1997 (TRODAT-1 and technepine), and [ 99m Tc]
`TRODAT-1 has succeeded in entering evalua-
`tion for clinical approval a few years later
`[ 64 – 66 ].
` From 2000 to the present, the range of radio-
`tracers for studying biochemical and pathophysi-
`ological molecular mechanisms has been
`expanding continuously. New targets of interest
`for neurological applications have been explored,
`among which are norepinephrine transporters
`([ 11 C]methyl reboxetine), neurokinin-1 ([ 18 F]
`SPA-RQ) and cannabinoid-1 ([ 18 F]MK-9470)
`receptors and Alzheimer-related proteins (beta-
`amyloid with [ 11 C]PiB (Pittsburgh compound B)
`and related fl uorine analogs, and more recently
`tau protein and alpha-synuclein with [ 18 F]
`THK5105) [ 67 – 71 ]. The concomitant advances
`in PET technology and the scanner proliferation
`in industrialized countries corroborated to estab-
`lish the role of imaging in both research and clin-
`ical settings to improve our understanding in
`diagnoses, monitoring disease progression, and
`the response to treatment.
` Unfortunately, relatively few radiotracers
`have been translated into the clinical setting, due
`to high requirements and complex procedures for
`getting the approval from authorities and, not
`least, because of the high costs of the required
`infrastructures. In addition, the utility of carbon-
` 11, incorporated in most of the developed com-
`pounds, is limited by its short radioactive
`half-life, and for this reason, its on-site produc-
`tion and use are essential. On the contrary, fl uo-
`rine- 18 radiotracers may be produced and
`distributed to local hospitals, making use of this
`technology more widely accessible. A notable
`and successful example on the evolution for a
`specifi c clinical need, although uncommon, is
`represented
`by
`the
`radiopharmaceuticals
`employed in amyloid PET imaging. The fi rst
`published experimental data using a carbon-11
`compound ([ 11 C]PiB) with affi nity for amyloid
`plaques has been followed by the development
`and commercialization of fl uorine-18 analogs
`([ 18 F]fl orbetapir, [ 18 F]fl orbetaben, and [ 18 F]fl ute-
`metamol) in less than 10 years [ 72 ].
`
`Petitioner GE Healthcare – Ex. 1014, p. 35
`
`

`

`36
`
`M. Riondato and W.C. Eckelman
`
` It is expected that in the future, brain imaging
`will continue to benefi t from new radiotracers
`and radiopharmaceuticals, although research
`activities appear to be less optimistic with
`respect to the initial enthusiastic consensus [ 73 ].
`However, the lack of appropriate radiotracers
`for unknown molecular brain mechanisms rep-
`resents one of the major challenges for radio-
`chemists
`in supporting Nuclear Medicine
`imaging to understand physiological processes
`and diseases and for application
`to drug
`development.
`
`4.3
`
` Radiotracer
`and Radiopharmaceutical
`Design for the Development
`of Brain Imaging Agents
`
` From the 1920s, when George Charles de Hevesy
`coined the term “radiotracer” paving the way for
`the application in biomedical sciences, many
`imaging agents have been developed and applied
`in Nuclear Medicine [ 74 ]. Over the years, brain
`imaging studies have evolved to include single-
`photon- emitting (SPECT) and positron-emitting
`(PET) radiopharmaceuticals particularly used in
`the evaluation of brain tumors, central motor dis-
`orders, and cognitive disorders.
` Based on their mechanism of action, SPECT
`and PET brain radiotracers are generally classi-
`fi ed in two groups according to their capability to
`perfuse cerebral tissues or to interact with specifi c
`substrates. The fi rst group comprises the substrate
`nonspecifi c agents able to cross BBB and trace
`dynamic processes for high-capacity systems.
`They represent an important class of radiotracers,
`which biodistribution correlates with cerebral
`blood fl ow or brain tissue permeability; thus, they
`are also defi ned as perfusion agents (e.g., [ 99m Tc]
`HMPAO and PET [ 15 O]water).
` The second group is referred to those radio-
`tracers with specifi city for biochemical targets
`susceptible to changes as function of disease
`states. These agents are dependent on the densi-
`ties of the interested molecular targets such as
`
`receptors, enzymes, and transporters. Since
`they are usually present at very low concentra-
`tions and are susceptible to saturation, these
`targets are defi ned as low-density-easily satu-
`rated sites. Lately, a major interest has been
`devoted to this class of radiotracers, due to their
`capability of detecting targets at the molecular
`level.
` Despite the relevant results achieved in
`research during the last decades, the range of
`radiotracers and radiopharmaceuticals used for
`brain imaging in clinical settings worldwide
`appears limited (Table 4.2 ). In 2013, Molecular
`Imaging and Contrast Agent Database (MICAD)
`reported 11 SPECT and almost 100 PET tracers
`that have been tested at least once in humans,
`with potential as brain imaging agents [ 75 ].
`However, a very few of them have reached the
`clinical state. This is consistent with the general
`reduced trend of approval of new pharmaceuti-
`cals (including radiopharmaceuticals) by the
`National Regulatory Authorities responsible for
`human medicines that shows a constant decline
`in approvals after 2000. Regulatory aspects and
`clinical development have to be considered the
`main reasons for such a few introductions,
`together with the economic aspects. An estimate
`of time and costs for the clinical development of
`diagnostic agents has been reported by Nunn and
`more recently by Zimmermann, who calculated
`that a radiopharmaceutical has a cost of €20–60
`million from the time the lead molecule is identi-
`fi ed and takes 7–9 years to develop (Fig. 4.1 )
`[ 76 , 77 ]. A conventional therapeutic drug has a
`higher cost, approximately €82–300 million to
`develop over 10–15 years, but the related market
`is by far larger than that of imaging agents, thus
`generating a much higher return on investment
`[ 78 ]. It is therefore evident that the commercial-
`ization of diagnostic imaging agents will not
`generate the same income in a comparable
`amount of time.
` In this scenario, academic investigators play a
`major role in the design and synthesis of diagnos-
`tic imaging agents whose development has to be
`in line with the emerging needs of the public
`
`Petitioner GE Healthcare – Ex. 1014, p. 36
`
`

`

`4 Radiopharmaceuticals
`
`37
`
` Table 4.2 Radiopharmaceuticals approved or registered by federal authorities
`
` Common names, acronyms, and nomenclature
`
` Process/target
`
` Common name
` Flow and perfusion
` [ 99m Tc]ECD
` [ 99m Tc]HMPAO
` [ 15 O]O 2
` [ 15 O]H 2 O
` [ 15 O]CO
` [ 81m Kr]Krypton
` [ 133 Xe]Xenon
` Tumor metabolism
` [ 18 F]FDG
` [ 123 I]IMT
` [ 11 C]Methionine
` [ 18 F]FET
` [ 11 C]Choline
`
` [ 99m Tc]-Bicisate
` [ 99m Tc]-Exametazime
`
` 2-Deoxy-2-fl uoro-D-glucose
` 3-Iodo-L-α-methyl tyrosine
` (S)-2-Amino-4-(methylthio)butanoic acid
` Fluoroethyltyrosine
` 2-Hydroxy-N,N,N-trimethylethanamonium
`
` Metabolic trapping
` Metabolic trapping
` Oxygen diffusion
` Water diffusion
` Red blood cell labeling
` Diffusion
` Diffusion
`
` Glucose metabolism
` Amino acid transport
` Amino acid transport
` Amino acid transport
` Cell membrane
`metabolism
` Cell membrane
`metabolism
` Lipid metabolism
` DNA synthesis
` Hypoxia
` P-glycoprotein
` Potassium analog
`
` Dopamine synthesis
`
` Dopamine transporter
`
` Dopamine transporter
`
` Dopamine transporter
`
` Dopamine transporter
`
` Dopamine D2/D3 receptor
`
` Serotonin transporter
`
` Dopamine D2 receptor
`
` Dopamine D2 receptor
`
`(continued)
`
` [ 18 F]Methylcholine
`
` 2-Fluorooxyethyl(trimethyl)azanium
`
` [ 11 C]Acetate
` [ 18 F]FLT
` [ 18 F]FMISO
` [ 99m Tc]MIBI
` [ 201 Tl]Thallium chloride
` Dopamine system
` [ 18 F]FDOPA
`
` [ 123 I]FP-CIT (DaTscan)
`
` [ 123 I]E-IA-F-CIT
`
` [ 99m Tc] TRODAT-1
`
` [ 123 I]Beta-CIT(DOPAScan)
`
` [ 123 I]Epidepride
`
` [ 123 I]ADAM
`
` [ 11 C]Raclopride
`
` [ 123 I]IBZM
`
` [1- 11 C]Acetate
` 3′-Deoxy-3′-fl uorothymidine
` Fluoranyl-3-(2-nitroimidazol-1-yl)propan2-ol
` [ 99m Tc]-Sestamibi
`
` (2S)-2-amino-3-(2-fl uoranyl-4,5- dihydroxyphenyl)
`propanoic acid
` Iofl upane(123I)
` 2-Carbomethoxy-8-(3-fl uoropropyl)-3-
`(4- iodophenyl)tropane
` Altropane(123I)
` N-Iodoallyl-2-carbomethoxy-3-(4- fl uorophenyl)
`tropane
` 2-[2-[[(3S,4R)-3-(4-chlorophenyl)-8-methyl-8-
`azabicyclo[3.2.1]octan-4-yl]methyl-(2- sulfi doethyl)
`amino]
`acetyl]azanidylethanethiolate;oxo- technetium-99
` Iometopane(123I)
` 2Beta-carbomethoxy-3beta-(4-iodophenyl)tropane
` N-[[(2S)-1-ethylpyrrolidin-2-yl]
`methyl]-5-iodo-2,3-dimethoxybenzamide
` 2-[2-[(Dimethylamino)methyl]phenyl]
`sulfanyl-5-iodanylaniline
` (S)-3,5-Dichloro-N-((1-ethylpyrrolidin-2-yl)
`methyl)-2-hydroxy-6-methoxy-(S)-3,5- dichloro- N-
`((1-ethylpyrrolidin-2-yl)
`methyl)-2-hydroxy-6-methoxybenzamide
` Iolopride(123I)
` N-[[(2S)-1-Ethylpyrrolidin-2-yl]
`methyl]-2-hydroxy-3-iodanyl-6- methoxybenzamide
`
`Petitioner GE Healthcare – Ex. 1014, p. 37
`
`

`

`38
`
`Table 4.2 (continued)
`
`M. Riondato and W.C. Eckelman
`
` Common name
` N-[ 11 C]Methylspiperone
`
` [ 11 C]Flumazenil
`
` [ 123 I]Iomazenil
`
` Common names, acronyms, and nomenclature
` 8-[4-(4-Fluorophenyl)-4-oxobutyl]-3-methyl-1-
`phenyl-1,3,8-triazaspiro[4.5] decan-4-one
` Receptor- and enzyme-binding ligands (other than for Dopamine system)
` [ 11 C]PK11195
` 1-(2-Chlorophenyl)-N-methyl-N-(1- methylpropyl)-
`3-isoquinolinecarboxamide
` 4H-Imidazo(1,5-a)(1,4)benzodiazepine-3- carboxylic
`acid, 8-fl uoro-5,6-dihydro-5-methyl-6- oxo-, ethyl
`ester
` Ethyl 7-iodo-5-methyl-6-oxo-4H- imidazo[1,5-a]
`[1,4]benzodiazepine-3-carboxylate
` 2-Fluoro-3-[2(S)-2-azetidinylmethoxy]pyridine
` N-[ 11 C]Methylpiperidin-4-yl acetate
`
` 2-[ 18 F]F-A85380
` [ 11 C]MP4A
` Plaque-binding ligands
` [ 11 C]PiB
`
` [ 18 F]Florbetapir (Amyvid)
`
` [ 18 F]Flutemetamol (Vizamyl)
`
` [ 18 F]Florbetaben (Neuraceq)
`
` Cisternography
` [ 111 In]Indium
`diethylenetriamine
`pentaacetic acid injection
`
` Process/target
` Dopamine D2/5-HT 2
`receptor
`
` Translocator protein
`(TSPO)
` GABA receptor
`
` GABA receptor
`
` nACh receptor
` AChE activity
`
` Plaque acceptor
`
` Plaque acceptor
`
` Plaque acceptor
`
` Plaque acceptor
`
` 2-(4′-[ 11 C]
`Methylaminophenyl)-6-hydroxybenzothiazole
` 4-{(E)-2-[6-(2-{2-[2-(18F)Fluoroethoxy]ethoxy}
`ethoxy)-3-pyridinyl]vinyl}-N-methylaniline
` 2-[3-(18F)Fluoro-4-(methylamino)
`phenyl]-1,3-benzothiazol-6-ol
` 4-{(E)-2-[4-(2-{2-[2-(18F)Fluoroethoxy]ethoxy}
`ethoxy)phenyl]vinyl}-N-methylaniline
`
` Sodium;2-[bis[2-[bis(carboxylatomethyl)amino]
`ethyl]amino]acetate;indium-111
`
` CSF transport
`
`
`
`DISCOVERY AND DEVELOPMENT OF
`DIAGNOSTICS
`
`Identification
`of a
`diagnostic
`opportunity
`
`Chemical
`synthesis
`
`Assays and
`preclinical tests
`
`lead
`optimization
`
`Clinical
`development
`Phases I, II
`and III
`
`Regulatory
`authorities
`approval and
`launch
`
`€€20-60 million, 7-9 years
`
` Fig. 4.1 Discovery and development process for a diagnostic (Adapted from FDA’s Critical Path Initiative, cost and
`timeline numbers taken from Nunn and Zimmermann)
`
`health system, but must be also economically
`sustainable for the diagnostic companies.
` It is remarkable that within the few approved
`SPECT and PET agents in the last decade, most of
`them are brain imaging radiopharmaceuticals,
`with a tremendous increase of interest in the devel-
`
`opment of PET tracers for the diagnosis of neuro-
`degenerative disorders. This shows that the current
`efforts, both from academia and industry, point
`toward a more accurate and early diagnoses of
`CNS pathologies in order to help clinical decisions
`that improve the effectiveness of medical care.
`
`Petitioner GE Healthcare – Ex. 1014, p. 38
`
`

`

`4 Radiopharmaceuticals
`
`39
`
`4.3.1
`
` Radiopharmaceuticals
`for High-Capacity Systems or
`for Low-Density-Easily
`Saturated Sites
`
` The design and the development of a radiophar-
`maceutical are strictly connected with its applica-
`tion: delineating a pathophysiological process or
`targeting a specifi c molecular structure.
` The majority of the technetium-99m radio-
`pharmaceuticals currently in use have been
`designed and developed for high-capacity sys-
`tems. They are formulated from commercially
`available “instant kits” and pertechnetate-99m
`obtained from 99 Mo/ 99m Tc generators. Each kit
`typically contains the ligand, the radionuclide has
`to be complexed, and an adequate quantity of
`reducing agent buffers to adjust the pH and to suit
`the labeling conditions, stabilizing agents and
`excipients. The radiotracer is thus obtained from
`the reaction between the ligands and the radionu-
`clide in an appropriate oxidation state, resulting
`in a new stable coordinated system. The integral
`chemical structure for each complex, composed
`by the radionuclide core and ligands, is respon-
`sible for pharmacokinetic and pharmacodynamic
`properties. [ 99m Tc]HMPAO and [ 99m Tc]ECD are
`examples of kit-formulated radiopharmaceuticals
`for brain imaging routinely prepared in Nuclear
`Medicine worldwide [ 29 , 30 ]. However, the
`amount of ligands contained in an “instant kit” is
`by far greater than that of technetium-99m, and it
`would saturate many low-capacity targets. This is
`the reason why these radiopharmaceuticals are
`primarily used for the imaging of high-capacity
`systems, such as regional cerebral blood fl ow,
`where saturation cannot be achieved. [ 99m Tc]-kit-
`based radiopharmaceuticals are covering over
`80 % of all Nuclear Medicine diagnostic proce-
`dures worldwide, with a noteworthy contribution
`to neuroimaging studies, although receptors and
`other molecular structures are subjects of major
`interest in brain imaging research at present.
` Radiolabeled agents with high specifi city for
`low-density-easily saturated sites are usually
`modeled on partial agonists and antagonists in
`the CNS therapeutic drug repertoire and lead
`compounds
`in
`the fi eld of pharmaceutical
`
`research. Once the chemical structure of a poten-
`tial new radiotracer has been identifi ed for a spe-
`cifi c biological target, the next step is to
`synthesize the desired compound by coupling an
`emitting nuclide suitable for imaging.
` Many radiolabeled compounds with selectiv-
`ity for receptors, enzymes, and transporters both
`for SPECT and PET brain imaging have been
`developed over more than 40 years of research.
`Among these, radiotracers based on positron
`emitters provide much useful information on
`neurophysiology and neuropharmacology of
`cholinergic, serotonergic, dopaminergic, GABA/
`benzodiazepine, opioid, and other neurotrans-
`mission systems [ 73 ]. Furthermore, PET method-
`ology offers several advantages over SPECT,
`such as a higher sensitivity, better temporal and
`spatial resolution, shorter imaging protocols, and
`a lower patient dosimetry [ 79 ]. On th