20240722_184813

SB vs ND 구분 고려하므로 좀 더 고급이지만, reference region 존재시만 사용 가능

BPND ("binding potential non-displaceable")

BPND: the ratio (at equilibrium) of specifically bound radioligand to that of nondisplaceable radioligand in tissue. BPND, 이건 사실 Non-displaceable에 대한 SB의 ratio임) nondisplaceable (ND) uptake is the sum of nonspecific (NS) and free ligand in tissue. BPND = fNS·Bmax/KD = (VT - VND)/VND unitless!

In vivo LCMS In vivo PET study (BPND is determined using brain slices of rat, NHP & Human by ARG), BPND at baseline, BPND by occupancy 둘 다 구해짐. Eg) (importatn) 201904 Paul McTQudade slide p19 right-hand side (Binding of PDE10A ligand [3H]MK-8193 in NHP brain slices. Non-displaceable binding determined by prior administration of selective PDE10A inhibitor, (Hostetler et al. 2016, PMID 26596571) 보면 이해 될 듯 -decrease of 100% BPND represents full block of the target Mouse는 뇌 너무 작아 cerebellum 에서의 상대적 값을 얻고, NHP에서 정확히 알게됨. If, Cbll: 1, SN: 2 → Then: NSB (=ND): 1, SB (=2-1) (=BPnd): 1, 결국 다음 둘은 같은 의미 구나. ≥2:1 (SN에서 cbll대비 두배이야 한다는 의미), BPND >1 (SB와 NSB가 동등하단 의미) BPND는 결국 SB, Signal to noise ratio 의 지표임. BPND = 'SB to NSB ratio' https://journals.sagepub.com/doi/10.1177/0271678X17692599

≥2:1 (BPND >1)

	VT	BPND
when	No reference region → arterial sampling, input function	Reference region available
	FEPPA Ghadery 2017, 2020: all Arterial sample, Vt	DPA714 BPND: i) Simplified Reference Tissue Model with cerebellum as reference input function, or ii) cluster model with pseudoreference region
TO	Displaceable binding	Self-blocking study 에서 구해짐 (이게 충분해야 임상에서 TO study 함)
	change in target density or RO in single subject), 이건 tracer 아니라 약의 성질 아닌가?) >15%	>70%	Occ(%) = 100 × (BPNDbaseline − BPNDdrug) / BPNDbaseline

Variability

TRV (test-retest value)	within-subject VARIABILITY	|OPtest − OPretest| / ((OPtest + OPretest)/2) × 100% Average variation of OP from two scans on the same subject without intervention	(McCluskey, 2020 #1994) <10%
coefficient of variation (COV)	Between-subject variability	SD/M × 100% Average variation of OP within a group	(McCluskey, 2020 #1994) <10%
ICC	Intraclass correlation coefficient	(BSMSS − WSMSS) / (BSMSS + (k − 1) × WSMSS) Comparison of reliability of within-subject variability to between-subject variability	(McCluskey, 2020 #1994) >0.8
Dynamic range		Eg. altered expression in disease state). A high dynamic range allows smaller alterations in a system to be accurately detected, thus increasing sensitivity. Tracers with low dynamic range (for example due to high nonspecific binding) may not be able to accurately determine even large alterations in target availability, rendering the tracer incapable of quantifying target accurately.

GOOD RESOURCE: (McCluskey et al. 2020, PMID)

Using, time-activity curves (simplified reference-tissue model) SRTM includes the three parameters R1, k2 and the binding potential

Quantify target expression (B_max) across species along with regional distribution to inform PET tracer viability

• B_max determination typically performed via tissue homogenate binding, with regional distribution assessed via whole tissue slices and in vitro autoradiography (ARG)
• Both B_max and ARG work can be done using ³H or ¹²⁵I labeled compounds
  • Compound does not have to be viable PET tracer candidate, as long as it is highly selective with low to moderate non-specific binding

PET Tracer Viability:

• Directly related to B_max
• Typically want the B_max/Affinity (K_D) ratio > 10

	Bmax (nM)			PET Tracer Tractability
	Rodent	NHP	Human
Target 1	<1	<1	<1	Low
Target 2	100	110	105	High
Target 3	200	220	25	Target tractable. Anticipate smaller specific PET signal in human as compared to preclinical species

CONFIDENTIAL

Regional Tissue Distribution:

• Is tissue expression of target homogenous or heterogenous?
• Availability of reference region

(Hostetler et al., 2016. doi: 10.1007/s11307-015-0910-0, Mol Imaging Biol (2016) 18:579) Binding of PDE10A ligand [³H]MK-8193 in NHP brain slices. Non-displaceable binding determined by co-incubating (Prior to tracer injection 이라는데?) with selective PDE10A inhibitor (THPP-1). High-density binding localized in the caudate-putamen and nucleus accumbens with lowest binding density in the cerebellum. Similar binding seen across species (rodent, NHP and Human). Takeda Pharmaceutical Company Limited

	R1	Binding potential (BPnd)	K2
	= relative tracer delivery, = tracer delivery ratio = ratio of transport rate from blood to brain (K1/K1')	ratio of bound concentrations to non-displaceable concentrations at equilibrium VS and VND are the specific and non-displaceable brain to plasma partition coefficients, respectively. BPND = VS/VND	Clearance, the rate constant for transfer to plasma from the free and non-specific concentration in the region of interest.
(Chauveau, 2009 #2663)	- R1 > 1 indicate a facilitated entry of the radiotracer in the target area (ipsilateral area) with respect to the reference area (contralateral area) - R1 affects mainly the distribution phase and have a limited influence on the BP	당연히 ↑ means good.

Variable	Criterion
Structure	Suitable for radiolabeling with a positron emitting radionuclide
in vitro affinity	Kd (IC50) < 10 nM. Preferable: Bmax/Kd ≥ 10, Minimum acceptance: Bmax/Kd ≥ 1
in vitro selectivity	High selectivity
non-specific binding (NSB)	Low non-specific binding. Higher fup/fub is better. Preferable: LogP or LogD <3
in vivo specific binding (SB)	Detectable level of SB (Acceptable signal-to-noise)
Brain exposure	Good permeability and no possible substrate of P-gp and BCRP (MDR/BCRP ratio < 2)
Metabolism	Parent tracer constitutes the main radiochemical entity in brain
Toxicity	Safe for administration in tracer doses

From McCluskey 2020

Basic description of common outcome parameters used in PET imaging studies

parameter	Full name	Equation	Description
	Percentage injected dose	% of injected dose / g of tissue	Percentage of injected radiotracer per unit volume (or weight) of tissue
	Standardised uptake value	%ID × 100 / subject weight	Weight corrected parameter of %ID
	Relative SUV	SUVtarget / SUVother	Ratio between SUV values between target and other regions
	Volume of distribution	CT / CP	Ratio of tracer concentration between tissue and plasma at equilibrium

Uncertain Spans

location	transcription	uncertainty
Top vertical row label	SB vs ND 구분 고려하므로 좀 더 고급이지만, reference region 존재시만 사용 가능	Rendered vertically at the left edge of the BPND row; readable but column structure (which row(s) it spans) is partially obscured by the photo crop.
이건 tracer 아니라 약의 성질 아닌가? annotation	(preserved as printed)	Author note inside the TO row challenging whether >15% reflects a tracer property or a drug property.
Brain-section figure (Hostetler 2016)	(NHP brain coronal sections labelled CPu, Ctx, Acb, GP, Cb, Bs, SN, Thal, Hipp)	Anatomical labels are small and one or two arrows fall on heatmap edges; preserved as evidence and the readable labels are listed in format_notes.
injection 이라는데? annotation	(preserved as printed)	Author parenthetical questioning the wording of prior administration vs co-incubating.
McCluskey 2020 outcome parameters table tail	(rows below Volume of distribution)	The table is cut at the bottom of the page; remaining rows continue on 20240722_184816.