RADIOPHARMACEUTICALS FOR IMAGING ALZHEIMER’S DISEASE

Ingrid Koslowsky, PhD Calgary Centre Foothills Medical Centre Calgary, AB Objectives

• To describe the characteristics of currently being used for imaging Alzheimer’s Disease (AD). • To describe the characteristics of radiopharmaceuticals recently approved for imaging AD. Brain Function Targets Radiotracer Cerebral Perfusion Cellular uptake [99mTc]Exametazine [99mTc]Bicisate Metabolism Cellular uptake [18F]FDG Cholinergic system Nicotinic & muscarinic [11C]Nicotine receptors; [11C]Benztropine, acetylcholinesterase [11C]Donepezil Dopaminergic system D1, D2 receptors, [11C]NNC756 transporters [123I- Serotoninergic system 5-HT1A 5-HT2A receptors; [11C]Way-100635 transporters [18F] [18F]

Histamine Receptors [11C]Doxepine Neuroinflammation Arachidonic acid metabolism [11C]Arachidonic acid Plaque formation Amyloid plaques [11C]PIB; [18F]-3′-FPIB [18F]-AV-1,[18F]-AV-45 [18F]AZD4694 NFT, tau [18F]FDDNP; [18F]T808; [18F]THK-523 Vallabhajosula S, Semin Nucl Med 41, 2011283 Radiolabelled Probes in Brain Imaging

• Perfusion (SPECT) • Metabolism (PET) • 99mTc-ECD • 18FDG (Bicisate , Neurolite) • 99mTc-HMPAO (Exametazine, Ceretec)

• Amyloid-β probes (PET) • 18F-

• 18F-

• 18F- Cerebral Perfusion Imaging Agents

Ceretec Neurolite (HMPAO, Exametazine) (ECD, Bicisate)

• Neutral, lipophilic ligands • Readily cross BBB Perfusion Agents: Pharmacokinetic Profile

99mTc-HMPAO 99mTc-ECD Max brain uptake (% inj dose) ~4% @ 20 min ~ 6.5% @ 5 min Mechanism of Retention Conversion to Metabolites trapped in hydrophilic complex cytosol Washout 15% over 2 min 20% over 1 h Optimum Imaging Time 40 - 90 min p.i. 20 – 45 min p.i. Excretion 40% urine (48 h); 70% urine (24 h); 30% hepatobiliary 10% hepatobiliary (48 h) (immediate) Perfusion Agents: Radiopharmaceutical Characteristics 99mTc-HMPAO 99mTc-ECD Typical RCP 80 to 90% > 90% Labelling 2-step (stabilized) 2-step • Addition of Methylene blue • Addition of Tc99m to as radical scavenger buffer • Addition of 99mTc eluate • Add ligand to Tc99m/buffer solution • Incubation: 30 min Other Fresh eluate required considerations Stabilized: Injection through filter Kit Stability 4 h (stabilized); (>) 6 h 30 min (unstabilized) 18FDG Mechanism of Uptake & Retention

Glucose metabolism

membrane

hexokinase glucose G G-6-phosphate glucose-6-phosphatase

hexokinase FDG FDG FDG-6-phosphate x glucose-6-phosphatase

facilitative glucose transport through Glut transporters 18FDG • Brain is an obligate glucose metabolizer • Marker of synaptic activity • Loss of synaptic activity  hypometabolism • Marker of neurodegeneration

• Not specific to AD • Pattern of hypometabolism can confirm or rule out AD

• Advantages over SPECT/perfusion agents • Superior image resolution with PET • Shorter scanning time • Metabolic changes typically precede recognizable perfusion changes in neurodegeneration

Cold Spring Harb Perspect Med 2012;2:a006213 18FDG: Procedure and Kinetic Profile

• Patient preparation • Fasting 4 to 6 h • Brain uptake of glucose highest post-prandial • Dose Injected: 370 MBq • Quiet, dim room 45 min to 1 h post injection (non stimulating environment) • Brain needs to be in resting state • Minimize muscle uptake • Accumulation in gray & white matter plateaus @ 90 min • Gray:white matter – 2:1 @ 90 min • Tissue concentration decreases after 120 min

• Tissue clearance t½: 9 h • Elimination: urinary • 20% excreted 2 h post injection

SNMMI procedure guidelines,JNM 2009 Radiolabelled probes for detection of AD

• Derivatives of fluorescent dyes • Thioflavin-T derivatives • Congo Red derivatives • Others (DDNP, acridine orange) • Derivatives of diethylstilboestrol (estrogen) Dye derivatives

Thioflavin-T 11C-PiB ()

CH CH3 S 3 11CH N H3C S 3 N+ N CH3 N H CH3

Positively charged molecule • Does not cross BBB 11C-PiB

• In vivo binding correlates tightly to Aβ levels (in vitro & in vivo)

• Minimal bind to neurofibrillary tangles

• Retention most prominent in frontal cortex of AD

• In areas unaffected by amyloid deposition ( e.g. cerebellum), retention equivalent in AD and controls

• 11C-PiB retention correlates inversely with cerebral glucose metabolism

Klunk B. J Cerebral Blood Flow Metab 25, 2005:1528 11C-PiB

• Imaging: • Dose: 370 MBq • Scan: 30 to 70 min post injection • Issues • Short half-life • Must be prepared on site (cyclotron) • (Clinical) Research tool

11C-PiB is the standard to which all other Aβ imaging agents are compared [18F]Flutemetamol (Vizamyl)

• FDA approved in 2013

• Similar kinetic profile to 11C-PiB

[18F]Flutemetamol • High correlation (r 0.91) with 11C-PiB in uptake and 11CH localization in brain images H3C S 3 N

N H 11C-PiB Stilbene Derivatives [18F]Florbetapir FDA Approved 2012 Composite r= 0.78

[18F]Florbetaben FDA Approved 2014 Composite r= 0.97 Diethylstilboestrol

Commons.wikimedia.org; Newdrugapprovals.org; Vandenberghe R. NeuroImage: Clinical 2, 2013: 497 Comparison Chart

Flutemetamol Florbetapir Florbetaben (Vizamyl) (Amyvid) (NeuraCeq) Lipophilic agents Uptake & Cross blood brain barrier Mechanism of Bind to amyloid-β plaque Action Does not bind to NFT Binding to tau not Selectivity over tau detected protein Dissociation 6.7 3.7 16 constant (nM) Plasma 12 to 15% remaining < 5% remaining 20 10% remaining 50 Clearance 60 min p.i. min p.i. min p.i (metabolites) (metabolites) (metabolites) < 2% 45 min p.i. Excretion 37% renal; Mainly hepatobiliary; 30% renal, 12 h p.i. 52% hepatobiliary; small amount in urine Comparison Chart

Flutemetamol Florbetapir Florbetaben (Vizamyl) (Amyvid) (NeuraCeq) Dose 185 MBq 370 MBq 300 MBq Mass (max) 20 ug 50 ug 30 ug Optimal imaging 90 min p.i. 30 to 50 min p.i. 45 to 130 min p.i. time Length of imaging 20 min image 10 min images 15 to 20 min AD drug None to date unknown None to date interactions EDE (mSv/dose) 5.9 7.0 5.8 Limitations to Amyloid-β Imaging • Probe retention not specific to AD • Moderate-to-frequent amyloid plaques found in patients with AD, • BUT may also be present in with other types of neurologic conditions as well as older people with normal cognition • Report as Aβ positive v.s. Aβ negative • Estimate plaque density • Aβ formation plateaus • Aβ images may not correlate with increasing cognitive decline • In contrast to FDG • Images are difficult to interpret • Special training program for interpretation • Loss of gray-white matter contrast • Require software to facilitate image analysis

Kepe V. J Alzheimer’s Dis 36, 2013:613. AD imaging: Access for Canadians??

• Uncertain how probes will be marketed in Canada • Licenced Cassette/kit? • Vendor – radiopharmacy partnerships? • Vendor provides expertise • Vendor assists with documentation • Will clinical trials be required? (Yes)

• Uncertain when probes will be marketed in Canada • Depends on the perceived need (public and payer) • Depends on cost of product • Depends on provincial reimbursement policies • Depends on regulatory hurdles Next wave of probes – Tau imaging

[ 18F]-T808, [ 1 F]-T807 [ 11C]PBB3

. Gao M. Bioorg Med Chem Lett, 24, 2014, 254. Autoradiography of [18F]-T808 and immunohistochemical staining of an AD patient’s brain. Zhang, W. J Alzheimer’s Disease, 31 2012: 601 Tau v.s. Aβ imaging in AD

[11C]PBB3 v.s. [11C]PiB

Data are displayed as parametric maps for SUVR.

Arrowheads represent binding to the hippocampal formation

Maruyama M. Neuron 79, 2013: 1094 Conclusion

• In Canada,18FDG is currently the most suitable agent for imaging dementia • Amyloid-β will add value to differential diagnosis of AD • Access to amyloid-β agents in Canada will depend on • Vendors willing to licence products in Canada • Perceived benefit by • Provincial health authorities • Public • Health professionals