A large body of research has established that amyloid plaques and neurofibrillary tau tangles—the pathological hallmarks of AD—often crop up years before a patient realizes something is awry. But the road to reliable preclinical AD biomarkers has proven long and difficult. The PET tracer Pittsburgh Compound-B (PIB) is perhaps furthest along in the journey, but the short half-life of its original radioisotope has restricted its use to academic medical centers with on-site cyclotrons and highly specialized personnel. The Human Amyloid Imaging conference, held 11 April 2008 in Chicago, offered glimpses of a handful of newer compounds being developed for broader clinical application.
The vast majority of published PET amyloid imaging studies have used [11C]PIB, a super-hot molecule with a high signal-to-noise ratio. Despite its robust performance, what keeps it from widespread use is the fact that it must be synthesized on-site and used for PET scanning within a half hour. However, compounds labeled with 18F, an isotope widely used in cancer imaging, are stable for up to six to eight hours after production, which would greatly extend their clinical access.
The only 18F amyloid PET tracers with published results at this point are 18F BAY94-9172 and FDDNP. 18F BAY94-9172 (also known as AV-1/ZK) was invented by Avid Radiopharmaceuticals, Philadelphia, Pennsylvania, and sublicensed to Bayer Schering Pharma; Chris Rowe of Austin Health, Melbourne, Australia, leads clinical studies of this compound (Rowe et al., 2008 and ARF related news story). FDDNP is an 18F-labeled PET tracer that labels both amyloid plaques and tau tangles in brain slices in vitro (Agdeppa et al., 2001) and can distinguish normal controls from subjects with MCI or AD (ARF related news story). Gary Small of the University of California, Los Angeles, provided an update on studies with FDDNP, as described later in this story.
Side-by-side comparisons of PET scans using [11C]PIB and 18F BAY94-9172 in the same subjects have not been formally published. But in historical comparisons of the two compounds using the same measuring technique, Rowe wrote via e-mail after the meeting that the mean cortical uptake of BAY94-9172 was 55 percent higher in AD patients than in healthy controls, compared with an 80 percent increase using [11C]PIB. Despite its lower signal relative to [11C]PIB, BAY94-9172 reliably distinguishes AD from frontotemporal dementia (FTD) and healthy controls, Rowe said, and only requires a 20-minute scan that produces easy-to-read images, so it has good potential clinically. Later this year, Bayer Schering Pharma will conduct multicenter Phase 2 trials with BAY94-9172 at sites in the U.S., Australia, Europe, and Japan.
Data on another Avid 18F amyloid tracer, AV-45, will be presented publicly for the first time by Dean Wong of Johns Hopkins University, Baltimore, Maryland, at the Society of Nuclear Medicine meeting in June, with another presentation to follow at ICAD in July. AV-45 is a pyridinyl analog of AV-1/BAY94-9172. Neither is a PIB derivative.
Meanwhile, a group led by Rik Vandenberghe of the Catholic University of Leuven, Belgium, has just completed the first Phase 1 studies of an 18F-labeled PIB derivative. 18F AH110690, a 3’ F-PIB analog dubbed 18F 3’-F-PIB, comes from the makers of [11C]PIB, i.e., Bill Klunk, Chet Mathis, and colleagues at the University of Pittsburgh. GE Healthcare is developing it for commercial use. In preliminary studies described by the Pittsburgh team in an abstract for the 2007 Society of Nuclear Medicine meeting, the new compound did nearly as well as [11C]PIB (standardized uptake values within 10 percent) at detecting amyloid in the precuneus and frontal cortex. It showed about 20 percent higher non-specific binding in white matter, but Klunk said that this does not preclude its ability to quantify cortical Aβ deposits.
Results from the single-center, non-randomized study of 18F 3’-F-PIB in Belgium were presented on a poster at the HAI meeting in Chicago. The first step of the study, which involved dynamic, whole-body PET scans on six healthy volunteers ages 51-73, established the compound’s effective dose (33.8mSv/MBq +/- 3.4 SD), showed it was safe, and set the injected activity to 185 MBq for the next stage of the study. This step aimed at optimizing the imaging procedure, and toward this goal performed dynamic brain PET scanning on three normal volunteers and three AD patients. All AD subjects showed higher specific binding in cortical regions—particularly in the frontal and lateral temporal cortex and posterior cingulate—relative to the healthy controls. Other brain areas, including the occipital cortex, had lower relative uptake ratios. Uptake ratios and distribution volume ratios (DVRs; see Part 1 in this series) were similar in white matter across all patients. Ongoing studies with an additional 10 participants (five AD, five normal) will be presented at ICAD in July, and Phase 2 trials are scheduled to start in June at three European sites.
A side note: while 18F radiolabeling methods were being worked out, GE Healthcare made an 11C-labeled version of 3’-F-PIB. This compound first went into humans two years ago in studies led by Juha Rinne at the Turku PET Centre in Finland. As presented at the HAI meeting on a poster, 11C 3’-F-PIB works well as an amyloid tracer. It shows increased uptake in the frontal, parietal, anterior cingulate, posterior cingulate, and occipital cortex of AD patients relative to healthy controls. The researchers found no significant change in 11C 3’-F-PIB uptake during AD progression over one year, consistent with previous experiments using [11C]PIB, which also show that PIB retention has plateaued by the time a person receives a clinical diagnosis of AD. The fact that 11C 3’-F-PIB did well in the Turku human studies gave GE Healthcare the go-ahead to continue working on the 18F-labeled 3’-F-PIB, the compound headed toward commercial use.
As mentioned above, the HAI audience also heard from Gary Small, who summarized recent findings and preliminary data from several studies with FDDNP, an amyloid PET tracer he co-invented. In a study of 59 non-demented ApoE4 carriers and non-carriers, his team found higher FDDNP binding in ApoE4 carriers, particularly in the medial temporal region. In a study involving patients with Down syndrome, which has been proposed as a model for studying AD, Small and colleagues observed that age and behavioral symptoms were correlated with global FDDNP signal—the older and/or more severe the behavioral symptoms, the higher the FDDNP signal. For further research on FDDNP, see Noda et al., 2008.
In a conversation with this reporter after the meeting, Klunk envisioned a day when amyloid imaging might do for AD what colonoscopy has done for colon cancer—reliably predict who will need intervention years down the road. Many studies, including those presented by keynote speaker David Bennett of Rush University Medical Center, Chicago, have converged on the idea that amyloid deposition is a very early event in the long path to AD diagnosis and that effective interventions will be needed before the MCI stage. We may not know what the future of AD treatment holds, but we do know, as Bennett reminded the audience in his talk title, that “in the beginning…there was amyloid.”—Esther Landhuis.
- Salzburg: Amyloid Imaging Update
- PET Probe Lights Up MCI, AD
- HAI Chicago: PIB in Healthy People
- HAI Chicago: Can PIB Predict Cognitive Decline?
- HAI Chicago: PIB and Aβ Show Regional Nuances and Sleep-Wake Rhythm
- Rowe CC, Ackerman U, Browne W, Mulligan R, Pike KL, O'Keefe G, Tochon-Danguy H, Chan G, Berlangieri SU, Jones G, Dickinson-Rowe KL, Kung HP, Zhang W, Kung MP, Skovronsky D, Dyrks T, Holl G, Krause S, Friebe M, Lehman L, Lindemann S, Dinkelborg LM, Masters CL, Villemagne VL. Imaging of amyloid beta in Alzheimer's disease with 18F-BAY94-9172, a novel PET tracer: proof of mechanism. Lancet Neurol. 2008 Feb;7(2):129-35. PubMed.
- Agdeppa ED, Kepe V, Liu J, Flores-Torres S, Satyamurthy N, Petric A, Cole GM, Small GW, Huang SC, Barrio JR. Binding characteristics of radiofluorinated 6-dialkylamino-2-naphthylethylidene derivatives as positron emission tomography imaging probes for beta-amyloid plaques in Alzheimer's disease. J Neurosci. 2001 Dec 15;21(24):RC189. PubMed.
- Noda A, Murakami Y, Nishiyama S, Fukumoto D, Miyoshi S, Tsukada H, Nishimura S. Amyloid imaging in aged and young macaques with [11C]PIB and [18F]FDDNP. Synapse. 2008 Jun;62(6):472-5. PubMed.